Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
1999-07-20
2001-04-03
Kifle, Bruck (Department: 1611)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
active
06211361
ABSTRACT:
FIELD
The present invention concerns a method for making debromohymenialdisine and analogs thereof, and analogs made by the method.
BACKGROUND
Debromohymenialdisine (DBH) 2 is a C
11
N
5
marine sponge alkaloid that was first isolated from an Okinawan sponge, Hymeniacidon sp.
Horne et al., “Synthesis of C
11
N
5
Marine Sponge Alkaloids: (±)-Hymenin, Stevensine, Hymenialdisine, and Debromohymenialdisine,”
J. Org. Chem.,
62:456-464, 456 (1997).
Known analogs of DBH include hymenin 4, stevensine 6, and hymenialdisine 8.
These natural products are the primary family members of the sponge metabolites that contain a fused pyrrolo[2,3-c]azepin-8-one ring system having either a 2-aminoimidazole or glycocyamidine appendage. Id.
Hymenin 4 has been shown to have potent &agr;-adrenoreceptor-blocking properties. Kobayashi, J. et al.,
Experientia
42; 1064 (1986); Kobayashi, J. et al.
The Alkaloids: Chemistry and Pharmacology,
41: 41-124 (1992); and Faulkner, D. J.,
J. Nat. Prod. Rep.,
13: 75 (1996). Moreover, DBH 2 can be used to treat subjects having osteooarthritis, which is a progressive, irreversible disease characterized by pain and loss of function caused by cartilage degradation. Chipman et al., U.S. Pat. No. 5,591,740 (the '740 patent), column 1, lines 7-18. Osteoarthritis can result in the complete erosion of weight-bearing articular cartilage, which may require total joint replacement. Id. Pro-inflammatory cytokine interluekin-1 (IL1) apparently plays a role in the cartilage matrix destructive processes observed in osteoarthritis. Pelletier et al.,
Sem. Arth. Rheum.,
20:12 (1991); and McDonnell, et al.,
Arth. Rheum.,
35:799 (1992).
Prior to the Chipman et al. invention described in the '740 patent, there were few, if any, therapeutic approaches that effectively slowed the clinical progression of osteoarthritis. The '740 patent, supra. The method for treating subjects having osteoarthritis described in the '740 patent comprises administering to individuals therapeutically effective amounts of DBH.
A commercially viable and efficient method for making DBH, and biologically active analogs thereof, is required to treat the number of patients having osteoarthritis, and other afflictions, who potentially might benefit from such treatments. Some methods are known for making hymenialdisine and DBH. See, for example, Horne et al.,
J. Org. Chem.
51:456-464 (1997), supra; Horne et al., U.S. Pat. No. 5,834,609, incorporated herein by reference; Horne et al., U.S. patent application Ser. No. 09/016,748, which is incorporated herein by reference; and Annoura et al., U.S. Pat. No. 5,621,099. These prior syntheses do not provide commercially viable methods for making DBH for several reasons, including (1) the yield of DBH is too low in the final step or steps of the synthesis, (2) the prior methods require too many synthetic steps overall, and (3) purification of the products. Therefore, despite these previous approaches, a more efficient and economically viable method for synthesizing bicyclic aminoimidazoles, such as DBH and analogs thereof, is needed.
SUMMARY
The present invention provides a method for making DBH and analogs thereof that addresses the problems associated with prior methods, such as by decreasing the number of steps of the synthesis and/or by increasing the overall yield of DBH or analogs thereof. The method of the present invention comprises providing hymenin 4, and then converting hymenin 4 into debromohymenialdisine 2, and analogs thereof, in the manner described herein.
As used herein, “analog” generally refers to compounds satisfying formulas stated in this application where R groups are hydrogen or aliphatic groups, particularly lower (10 carbon atoms or less) alkyl groups, X groups are hydrogen or halogen, particularly bromine, and combinations thereof. “Analog” also can refer to compounds having different ring structures, such as those exemplified by hymenin 4, stevensine 6, hymenialdisine 8, and the formulas provided herein.
Unless stated otherwise, variable groups on formulas provided in this application are as follows: C
1
and C
2
are carbon atoms bonded together by a single bond or a double bond; R is independently selected from the group consisting of hydrogen and lower aliphatic groups, particularly lower alkyl; R′ is selected from the group consisting of hydrogen, lower aliphatic, particularly lower alkyl, and alkoxy, particularly lower alkoxy; and X is independently selected from the group consisting of hydrogen and halogen.
One embodiment of the present method for converting hymenin 4 to debromohymenialdisine 2 and analogs thereof comprises first forming a compound having Formula 1 or Formula 2 below. With reference to Formula 1,
X is hydrogen when C
1
and C
2
are carbon atoms in a single bond and is a halogen when C
1
and C
2
are carbon atoms in a double bond. With reference to Formula 2,
X is independently selected from the group consisting of hydrogen and halogen other than bromine. If C
1
and C
2
are carbon atoms in a single bond, converting hymenin to debromohymenialdisine can comprise first providing a compound having Formula 3
where X is independently selected from the group consisting of hydrogen and halogen when any one of R is lower alkyl and is hydrogen when R is hydrogen. One example of a compound having Formula 3 is Compound 10
Compound 10 can be converted to debromohymenialdisine 2 by reaction with a halogen, such as bromine, typically in the presence of an acid, such as methane sulfonic acid. Converting Compound 10 to debromohymenialdisine 2 in this manner provides a distinct advantage over prior syntheses in that such approach is substantially more efficient than prior syntheses.
The method of the present invention also can comprise providing a compound having Formula 4
and then converting such compounds to compounds having Formula 3. One example of a compound having Formula 4 is Compound 12
Compounds having Formula 4 typically are converted to compounds having Formula 5
In such cases, the method can comprise providing a compound where all R and X groups are hydrogen in Formula 5, and converting comprises first forming the compound having Formula 3 with all R and X hydrogen by reaction with, for example, hydrogen and a catalyst, and then forming debromohymenialdisine 2.
Providing a compound having Formula 3 can be accomplished by first providing a compound having Formula 2 where X is halogen, and then converting the compound having Formula 2 to a compound having Formula 3 where R and X are hydrogen. One example of a compound having Formula 2 where R is hydrogen and X is bromine is Compound 26
Compound 26 can be converted to a compound having Formula 3 by heating the compound in an acidic aqueous solution, such as an acetic acid solution.
Converting a compound having Formula 2 to a compound having Formula 3 also can comprise forming Compound 28
and then reacting such compound with hydrogen and a catalyst. The present invention also can comprises converting hymenin directly, i.e., without any intermediate steps, to a compound having Formula 3, such as Compound 28. This provides a substantial advantage with respect to known syntheses, which require forming additional intermediates between hymenin and Compound 28.
C
1
and C
2
of Formula 1 also can be connected by a double bond, such as with Compound 30
Compound 30, and analogs thereof, can be directly converted to debromohymenialdisine 2 using hydrogen and a catalyst, including metal-based catalysts, particularly palladium-based catalysts and platinum-based catalysts, Lindlar's catalyst and Raney nickel. Such compounds also can be converted to debromohymenialdisine 2 using a metal and a mineral acid, such as zinc and hydrochloric acid. Alternatively, Compound 30 can be converted to Compound 10, which is then subsequently converted to debromohymenialdisine 2 by reaction with a halogen in the presence of an acid.
Still another embodiment of the method of the present invention comprises forming a compound having Formu
Horne David A.
Yakushijin Kenichi
Kifle Bruck
Klarquist Sparkman Campbell & Leigh & Whinston, LLP
State of Oregon acting by and through The Oregon State Board of
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