Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-12-26
2002-01-01
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S292000, C546S070000, C546S084000
Reexamination Certificate
active
06335346
ABSTRACT:
This application is the national phase of PCT/FR00/01123, filed Apr. 27, 2000.
The present invention relates to novel pyrrolo[3,4-b)quinoline derivatives of general formula I:
in which X represents an oxygen atom or a sulfur atom,
represents a group of formula:
R
1
represents a lower alkyl radical containing from one to three carbon atoms, a lower cycloalkyl radical containing from three to six carbon atoms or R
1
represents a lower alkyl radical linked to R
4
to form a 6-atom ring containing 0, 1 or 2 unsaturations,
R
2
, R
3
, R
4
and R
5
represent, independently of each other, a hydrogen atom, a lower alkyl group containing from one to three carbon atoms, a lower cycloalkyl group containing from three to six carbon atoms or a phenyl group, the corresponding racemic mixtures, as well as the pure enantiomers thereof or mixtures thereof in all proportions and the pharmaceutically acceptable salts thereof.
The term “lower alkyl” means linear or branched C
1
-C
3
alkyl residues chosen more particularly from methyl, ethyl, n-propyl, isopropyl and cyclopropyl groups.
When the derivatives comprise at least one asymmetric carbon, the present invention relates to the corresponding racemic mixtures, as well as to the pure enantiomers thereof or mixtures thereof in all proportions.
The therapeutically acceptable salts of the derivatives according to the invention are common organic or inorganic salts of the art, the hydrochlorides, tosylates, mesylates and citrates, as well as solvates such as the hydrates or hemihydrates of the compounds of general formula I.
The present invention more particularly relates to the derivatives of general formula I for which X preferably represents an oxygen atom or a sulfur atom.
Preferentially, R
1
advantageously represents a lower alkyl radical, optionally linked to R
4
to form a 6-atom ring, or a methyl, ethyl, n-propyl, isopropyl or cyclopropyl group.
Various pyrroloquinoline derivatives have been described in the prior art as synthetic intermediates by:
I. Pendrak, R. Winttrock, W. D. Kingsbury, J. Org. Chem, Vol. 60, No. 9, 1995, pages 2912-2915. T. Sugasowa, T. Toyoda, K. Saskura, Tetrahedron. Lett, No. 50, pages 5109-5112; J. M. D. Fortunak, A. R. Mastrocola, M. Mellinger, J. L. Wood, Tetrahedron. Lett; Vol. 35, No. 32, pages 5763-5764; D. P. Curran, H. Liu, H. Josien, Tetrahedron Lett, Vol. 52, No. 35, pages 11385-11404; J. M. D. Fortunak, A. R. Mastrocola, M. Mellinger, N. J. Sisti, J. L. Wood, Z. P. Zhung Tetrahedron. Lett; Vol. 37, No. 32, pages 5683-5686; D. L. Comins, J. K. Seha, J. Org. Chem, Vol. 61, No. 26, pages 9623-9624; A. I. Meyers et al., J. Org. Chem, Vol. 38, No. 8, 1993; S. Danishefsky, R. Volkmann, S. B. Horwitz, Tetrahedron Lett, No. 27, 1973, pages 2521, 2524; G. Stork, A. G. Schultz, J. Am. Chem. Soc, Vol. 93, No. 16, 1971; J. H. Rigby, D. M. Danca Tetrahedron Lett, Vol. 38, No. 28, 1997, pages 4969, 4972; M. Kitajima, S. Mosomoto, H. Takayama, N. Aimi, Tetrahedron. Lett, Vol. 38, No. 24, 1997, pages 4255-4258; M. Boch, T. Korth, J. M. Nelke, D. Pike, H. Radunz, Chem. Ber, 105, 1992, pages 2126-2142; M. Naoko, S. Takumchi, K. Yoshinori, S. Tako, Synlett, 1997, pages 298-300; J. M. D. Fortunak, A. R. Mastrocola, M. Mellinger, N. J. Sisti, J. L. Wood, Z. P. Zhung Tetrahedron. Lett; Vol. 37, No. 32, pages 5679-5682; I. Pendrak, R. Winttrock, W. D. Kingsbury, J. Org. Chem., Vol. 60, No. 9, 1995, pages 2912-2915; J. Warneke, E. Winterfeldt, Chem. Ber, 105, 1972, pages 2120-2125.
T. Yaegashi et al. (CA. 157128, 960307); S. Sawada et al. (EP 296612, 881228); B. R. Vishnuvajjala et al. (U.S. Pat. No. 4,943,579, 900724); H. Akimoto et al. (EP 556585, 930825); E. Bombardelli et al. (EP 685481, 951206) and E. Bombardelli, L. Verotta (PCT INT Appl. WO 97 43, 290) have disclosed pyrroloquinoline derivatives which have therapeutic activity, although this activity is not hypnotic or sedative activity.
The present invention relates to the pyrrolo[3,4-b]quinoline derivatives of general formula I as defined above.
The derivatives of general formula I, for which X represents an oxygen atom, can be obtained directly by oxidizing the compounds of general formula II
for which R
1
and A are defined above, with oxygen in the presence of a base such as sodium hydride or potassium tert-butoxide, or with a periodate.
The sulfur analogs of general formula I (X=S) are obtained from the corresponding oxygen derivatives of formula I (X=O) by the action of Lawesson's reagent, or by the action of phosphorus pentasulfide.
The examples which follow of preparations of derivatives according to the invention illustrate the present invention.
Examples of derivatives of general formula I, for which:
A) X represents an oxygen atom and
represents a group of formula
when R
4
and R
5
each represent a hydrogen atom, are given in Table I below
TABLE I
Example
—R
1
1
—CH
3
2
—(CH
2
)
2
—CH
3
3
when R
1
and R
4
are linked to form a ring corresponding to formula III
are given in Table II below
TABLE II
Example
—R
5
4
—CH
2
—CH
3
5
B) X represents an oxygen or sulfur atom, and
represents a divalent radical of formula
when R
3
, R
4
and R
5
each represent a hydrogen atom and R
1
represents a methyl radical
are given in Table III below
TABLE III
Example
X
−R
2
6
O
—H
7
S
—H
8
O
—CH
3
when R
1
and R
4
are linked to form a ring corresponding to formula IV, R
2
represents a hydrogen atom and X represents an oxygen atom
are given in Table IV below
TABLE IV
Example
R
3
−R
5
9
H
—CH
2
—CH
3
10
—CH
2
—CH
3
—CH
2
—CH
3
REFERENCES:
patent: 4943579 (1990-07-01), Vishouvajjala et al.
patent: 2157128 (1995-08-01), None
patent: 0 296 612 (1988-12-01), None
patent: 0 296 612 (1988-12-01), None
patent: 0 556 585 (1993-08-01), None
patent: 0 685 481 (1995-12-01), None
patent: 0 685 481 (1995-12-01), None
patent: WO/96/08490 (1996-03-01), None
patent: WO/97/43290 (1997-11-01), None
International Search Report for PCT/FR00/01123.
Pendrak et al.; Synthesis and Anti-HSV Activity of Methylenedioxy Mappicine Ketone Analogs;J. Org. Chem.1995, 60:2912-2915.
Sugasawa et al.; A Total Synthesis of dl-Campotothecin;Tetrahedron Letters1972, 50:5109-5112.
Fortunak et al.; Preparation of Mappicine Ketones from Camptothecins: Chemistry of the Camptothecin E Ring;Tetrahedron Letters1994, 35:5763-5764.
Curran et al.; Tandem Radical Reactions of Isonitriles with 2-Pyridonyl and Other Aryl Radicals: Scope and Limitations, and a First Generation Synthesis of (±)-Campotothecin;Tetrahedron1996, 52:11385-11404.
Fortunak et al.; Novel Synthesis of Camptothecin Alkaloids, Part 2.1Concise Synthesis of (S)-Camptothecins;Tetrahedron Letters1996, 32:5683-5686.
Comins et al.; Concise Synthesis of Mappicine Ketone and (±)-Mappicine;J. Org. Chem.1996, 61:9623-9624.
Meyers et al.; A Total Synthesis of Camptothecin and Deethyldeoxycamptothecin;J. Org. Chem.1973, 38(11):1974-1982.
Danishefsky et al.; Isocamptothecin;Tetrahedron Letters1973, 27:2521-2524.
Stork et al.; The Total Synthesis of dl-Camptothecin;J. Amer. Chem. Soc.1971, 4074-4075.
Rigby et al.; Vinyl Isocyanates in Alkaloid Synthesis. Camptothecin Model Studies;Tetrahedron Letters1997, 38(28):4969-4972.
Kitajima et al.; Isolation and Partial Synthesis of 3(R)- and 3(S)-Deoxypumiloside; Structural Revision of the Key Metabolite from the Camptothecin Producing PlantOphiorrhiza pumila1997, 38(24):4255-4258.
Bock et al.; Die Biogenetisch Orientierte Totalsynthese von DL-Camptothecin und 7-Chlor-Camptothecin;Chem. Ber.1972, 105:2126-2142.
Murata et al.; Synthesis of Functionalized Heteroaromatics: Application to Formal Total Synthesis of Camptothecin;SYNLETT1996, 298-300.
Fortunak et al.; Novel Syntheses of Camptothecin Alkaloids, Part I. Intramolecular [4+2] Cycloadditions of N-arylimidates and 4H-3,1-benzoxazin-4-ones as 2-Aza-1,3-Dienes;Tetrahedron Letters1996, 37(32):5679-5682.
Warneke et al. ;Die autoxydative Indol-Chinolon-Umwandlung eines Camptothecin-Modells;Chem. Ber.1972, 105:2120-2125.
Fourtillan Jean-Bernard
Fourtillan Marianne
Jacquesy Jean-Claude
Jouannetaud Marie-Paule
Karam Omar
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Huang Evelyn Mei
MACEF
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