Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-03-12
2000-08-29
Seaman, D. Margaret
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546 82, C07D22106, C07D49800
Patent
active
061111104
DESCRIPTION:
BRIEF SUMMARY
The present invention belongs to the fields of organic chemistry, pharmaceutical chemistry and chemical manufacture, and provides a convenient and economical process for preparing benzo[f]quinolinones which are useful as 5.alpha.-reductase inhibitors and provides intermediate compounds for the preparation of such pharmaceuticals.
A currently active field of pharmaceutical research is the inhibition of 5.alpha.-reductase, the enzyme which converts testosterone to dihydro-testosterone, a more potent androgen. It has been demonstrated that inhibitors of 5.alpha.-reductase can block the formation of dihydrotestosterone and ameliorate a number of highly undesirable conditions, including male pattern baldness and benign prostatic hypertrophy. Audia et al., have disclosed a series of benzo[f]quinolinone compounds which are 5a-reductase inhibitors. See: U.S. Pat. Nos. 5,239,075 and 5,541,190; Tet. Let., 44, 7001 (1993); J. Med. Chem., 36, 421 (1993); and European Patent Publication 0703221.
The present invention provides a novel process for preparing benzo[f]quinolinones which are effective inhibitors of 5.alpha.-reductase. The present process is more efficient than prior processes, is amenable to large-scale synthesis, and avoids the formation of unwanted by-products. This invention also provides intermediate compounds for the preparation of such pharmaceuticals.
The present invention provides a novel process for preparing benzo[f]quinolinones and provides intermediates useful in preparing benzo[f]quinolinones. More specifically, the present invention is directed to a process for preparing a compound of the formula I ##STR1## wherein R.sup.1 represents: 2-nitrophenyl, 4-nitrophenyl, 2-cyanophenyl, 4-cyanophenyl, 2-nitronaphthyl, 4-nitronaphthyl, 2-cyanonaphthyl, 4-cyanonaphthyl, 2-quinolinyl, 4-quinolinyl, 7-quinolinyl, 1-isoquinolinyl, 3-isoquinolinyl, 8-isoquinolinyl, 2-quinoxalinyl, 2-pyridinyl, 4-pyridinyl, 2-pyrazinyl, 2-naphtho[2,3]-dithiazolyl, 2-naphtho[1,2-d]thiazolyl, 9-anthryl, 2-thiazolyl, 2-benzimidazolyl, 1-benz[g]isoquinolinyl, 8-benz[g]isoquinolinyl, 5-1H-tetrazolyl, 2-quinazolinyl, 2-thiazolo[4,5-b]pyridinyl, 4-10H-pyridazino[3,2-b]-2-quinazolinyl, 2-1,4-benzodioxinyl, 2-triazine, 2-benzoxazine, 4-benzoxazine, 2-purine or 8-purine;
wherein the above R.sup.1 groups are unsubstituted or substituted with 1-3 functionalities chosen from the group consisting of trifluoromethyl, trifluoroethoxy, C.sub.1 -C.sub.4 alkyl, trifluoromethoxy, hydroxy, C.sub.1 -C.sub.3 alkoxy, nitro, C.sub.1 -C.sub.3 alkylthio, C.sub.1 -C.sub.6 alkanoyl, phenyl, oxo, phenoxy, phenylthio, C.sub.1 -C.sub.3 alkylsulfinyl, C.sub.1 -C.sub.3 alkylsulfonyl, cyano, amino, C.sub.1 -C.sub.3 alkylamino, diphenylmethylamino, triphenylmethylamino, benzyloxy, benzylthio, (mono-halo, nitro or CF.sub.3)benzyl(oxy or thio), di(C.sub.1 -C.sub.3 alkyl, C.sub.3 -C.sub.6 cycloalkyl, or C.sub.4 -C.sub.8 cycloalkylalkyl)amino, (mono-C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy or halo)(phenyl, phenoxy, phenylthio, phenylsulfonyl or phenoxysulfonyl), C.sub.2 -C.sub.6 alkanoylamino, benzoylamino, diphenylmethylamino(C.sub.1 -C.sub.3 alkyl), aminocarbonyl, C.sub.1 -C.sub.3 alkylaminocarbonyl, di(C.sub.1 -C.sub.3 alkyl)aminocarbonyl, halo-C.sub.1 -C.sub.6 alkanoyl, aminosulfonyl, C.sub.1 -C.sub.3 alkylaminosulfonyl, di(C.sub.1 -C.sub.3 alkyl)aminosulfonyl, phenyl(oxy or thio)(C.sub.1 -C.sub.3 alkyl), (halo, C.sub.1 -C.sub.3 alkyl or C.sub.1 -C.sub.3 alkoxy)phenyl(oxy or thio)(C.sub.1 -C.sub.3 alkyl), benzoyl, or (amino, C.sub.1 -C.sub.3 alkylamino or di(C.sub.1 -C.sub.3 alkyl)amino)(C.sub.1 -C.sub.3 alkyl).
An aspect of the invention comprises: converting a ketone of the formula ##STR2## wherein R is halogen, preferably bromo or iodo; to a protected ketal, preferably employing trimethylsilyltrifluoromethanesulfonate and 1,3-bis-trimethylsilyloxy propandiol in methylene chloride; as, n-butylithium and a sulfur transfer reagent, such as, dimethyl disulfide, to afford an S-methylated ketal compound; and methyl-thiotetralone compound of the formula II #
REFERENCES:
patent: 5239075 (1993-08-01), Audia
patent: 5334767 (1994-08-01), Audia
patent: 5550134 (1996-08-01), Audia et al.
patent: 5629007 (1997-05-01), Audia
patent: 5635197 (1997-06-01), Audia
patent: 5670512 (1997-09-01), Audia
patent: 5710163 (1998-01-01), Audia
Young et al, The Methyl Group as a Protecting Group for Arylthiols: A Mild and Efficient Method for the Conversation of Methyl Aryl Sulfides to Arylthiols; 25:17, 1753-1756 (1984).
Chem. Abstr., vol. 126, No. 1, Jan. 6, 1997, p. 891, col. 1, Abst. No. 8006x.
Chem. Abstr., vol. 125, No. 1, Jul. 1, 1996, p. 1170, col. 1, Abst. No. 10633x.
Brennan John
Doecke Christopher William
Heath Perry Clark
Patterson Lawrence Edward
Udodong Uko Effiong
Eli Lilly and Company
Sayles Michael J.
Seaman D. Margaret
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