Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-11-13
2003-08-26
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S530000, C514S590000, C514S614000, C546S325000, C560S027000, C560S029000, C564S151000, C564S036000, C564S250000
Reexamination Certificate
active
06610715
ABSTRACT:
This application is the national phase under 35 U.S.C. §371 of PCT International Application No. PCT/KR99/00264 which has an International filing date of May 28, 1999, which designated the United States of America and was published in English.
FIELD OF THE INVENTION
The present invention relates to novel cathecol hydrazone derivatives which inhibit the enzymatic activity of phosphodiesterase IV or tumor necrosis factor. These compounds may be useful in prevention or treatment of bronchial asthma, arthritis, bronchitis, chronic atretic airway, psoriasis, allergic rhinitis, dermatitis, AIDS, Crohn's disease, septicemia, septic shock, other inflammatory diseases such as cachexia, TNF related diseases, etc. Also, the present invention relates to a method for producing said compounds and a pharmaceutical composition containing said compound.
BACKGROUND OF THE INVENTION
Phosphodiesterase IV is an enzyme that specifically hydrolyzes cAMP (cyclic adenosine 3′,5′-monophosphate) into inactive adenosine 3′,5′-monophosphate. The cAMP has been shown to be a second messenger mediating the cellular responses to external stimuli and to act as relaxing or contradicting bronchial muscles.
The inhibition of phosphodiesterase IV leads to the prevention of broncospasm by maintaining the concentration of cAMP and also induces an anti-inflammation. Therefore, compounds that inhibit phosphodiesterase IV should be effective in treating asthma and the like diseases.
It is known that tumor necrosis factor (TNF) is implicated in infectious disease such as cachexia and autoimmune disease. Also, TNF appears to act as a primary mediator for inflammatory reaction such as septicemia and septic shock.
Therefore, it is expected that compounds with the inhibitory activity against phosphodiesterase IV or TNF will be pharmaceutically valuable and there is always a need to develop new compounds which inhibit phosphodiesterase IV and TNF.
Many compounds have been suggested as inhibitors of phosphodiesterase IV and TNF. For example, EP 470,805 of American Home Product describes oximcarbamate and oximcarbonate of formula:
wherein R is C
3-7
alkyl or C
3-7
cycloalkyl, R
1
is halogen or lower alkyl, and R
2
is amino, lower alkylamino, arylamino, lower alkoxy or aryloxy.
U.S. Pat. No. 5,393,798 of SmithKline Beecham Corporation describes phenylalkyl oxamide compound of formula:
wherein R
1
is C
4-6
cycloalkyl, X is YR
2
halogen in which Y is oxgen or sulfur, or lower alkyl, R
3
and R
5
are independently OR
7
, R
4
is hydrogen or C
1-2
alkyl, R
6
is OR
7
or NR
7
OR
7
, and R
7
is hydrogen or C
1-3
alkyl.
SUMMARY OF THE INVENTION
The present invention provides novel cathecol hydrazone derivatives of formula I:
or pharmaceutically acceptable salts thereof, wherein
R
1
is C
1-7
alkyl or C
3-7
cycloalkyl;
R
2
is hydrogen, hydroxy, C
1-5
alkyl or —CH
2
CH
2
C(═O)NH
2
;
R
3
and R
4
are independently hydrogen, C
1-7
alkyl, —C(═X)—R
5
, or 2-, 3- or 4-pyridyl, prymidyl or phenyl substituted with one or two selected from a group consisting of halogen, C
1-6
alkoxy, nitro, trifluoromethyl, C
1-6
alkyl and carboxyl, or R
3
and R
4
are directly bonded by C
3-4
containing oxygen, sulfur or nitrogen to form a heterocyclic ring, X is oxygen, sulfur or NH, and R
5
is C
1-7
alkyl, —NHR
6
, CONH
2
or 2-, 3- or 4-pyridyl, prymidyl or phenyl substituted with one selected from a group consisting of halogen, C
1-6
alkoxy, nitrile, trifluoromethyl, C
1-6
alkyl and carboxyl, and R
6
is hydrogen, hydroxy, NH
2
, C
1-5
alkoxy, C
1-5
alkyl, pyridyl or phenyl.
DETAILED DESCRIPTION OF THE INVENTION
The compound of formula I can be present as optical isomers or stereoisomers. Thus, the present invention includes such isomers and mixtures thereof.
The present invention provides a pharmaceutical composition for inhibiting phosphodiesterase IV or TNT which comprises a compound of formula I and a pharmaceutically acceptable carrier.
The compound of formula I can be prepared by the following reaction scheme I:
wherein R
1
, R
2
, R
3
and R
4
are the same as defined above.
Some derivatives were synthesized by a known method (J. Med. Chem., 1994, 37, 1696). Hydrazine compounds were synthesized in yield of 60% to 90% in alcohol solvent using acid catalyst (Tetrahedron Lett. 1994, 35, 3711).
REFERENCES:
patent: 3753680 (1973-08-01), Tilles
patent: WO 98/47869 (1998-10-01), None
Prescott et al.; “Some New Thiosemicarbazones as Potential Chemotherapeutic Agents Indarolythiosemicarbazones” Int. Congr. Chemother., Proc., 5th1967, 1(1), 23-33; Chem. Abstract, vol. 70, No. 21, May 26, 1969, pp. 339, the abstract No. 96701y.
Richard et al., “Oxidation of Aldehyde N,N-dialkyl-hydrazones with Hydrogen Peroxide . . . ”, J. Org. Chem. 31(21), 4100-2 (1966), Chem. Abstract, vol. 66, No. 7, Feb. 13, 1967, pp. 2696, the abstract No. 28492y.
Prescoot et al., “Potential Antitumor Agents. Derivatives of 2-hydrazino-5-nitropyridine”, J. Pharm. Sci. 1970, 59(1), 101-4, Chem. Abstract, vol. 72, No. 15, Apr. 13, 1970, pp. 225, 226, the abstract No. 77139w.
Kozlow et al., “Interaction of Schiffbases with Phenylhydrazine and its Nitro Derivatives”, Tr. Prem. Sel.-Khoz. Inst. 1970, No. 68, 101-4 Chem. Abstract, vol. 77, No. 17,23.10.72, pp. 412, the abstract No. 113968e.
Chupakhin, “Reaction of Acridinium Salts with Phenylhydrazones and Phenylhydrazides,” Khim. Geterotsikl. Soedin, 1975, (3), 387-91, Chem. Abstract, vol. 83, No. 3, Jul. 21, 1975, pp. 494, the abstract No. 28073p.
Kachroo et al., “Synthesis of Some Substituted-1,3,4-oxadiazoles, Their Antibacterial and Antiamebic Activity”, Natl. Acad. Sci. Lett(India) 1991, 13(4), 125-6 Chemical Abstract vol. 115, No. 5, Aug. 5, 1991, pp. 832, the abstract No. 49539g.
Chen et al.: Acta Cystallogr. Sect. C, Cryst. Struct. Commun. 1997, C 53 (6), 775-77, vol. 127, No. 4, Jul. 28, 1997, p. 1388.
Kim Eui Kyung
Kim Jong Hoon
Lee Kwang Hyuk
Rhee Chung Keun
Shin Jae Kyu
Anderson Rebecca
Cheil Jedang Corporation
McKane Joseph K.
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