CA2245758C - Benzo[c]quinolizine derivatives, their preparation and use as 5.alpha.-reductases inhibitors - Google Patents
Benzo[c]quinolizine derivatives, their preparation and use as 5.alpha.-reductases inhibitors Download PDFInfo
- Publication number
- CA2245758C CA2245758C CA 2245758 CA2245758A CA2245758C CA 2245758 C CA2245758 C CA 2245758C CA 2245758 CA2245758 CA 2245758 CA 2245758 A CA2245758 A CA 2245758A CA 2245758 C CA2245758 C CA 2245758C
- Authority
- CA
- Canada
- Prior art keywords
- benzo
- quinolizine
- 8alkyl
- group
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention refers to benzo[c]quinolizine derivatives of general formula (I), their pharmaceutically acceptable salts or esters, processes for their preparation and pharmaceutical compositions containing them.
Description
Benzo[c]quinoiizine derivatives, their preparation and use as 5a-reductases inhibitors.
Field of the invention The present invention refers to benzo[c]quinolizine derivatives of general formula (I) R' ~~-SnW)n i: ~,~ (I) ~' a g a b .1 ~f ~ ,.
''d T ! T
z Rs wherein:
R1, R2, R3, R4, R6, same or different, are chosen in the group consisting of: H, C1_$alkyl. C2_$alkenyl, CZ_8alkiny7., cycloalkyl, aryl, heterocycle, halogen, CN, azide. NRR', C1_$alkylamino, arylamino, C1_$alkyloxy, aryloxy, C00R, GONRR' wherein R and R', same or different, are chosen in the group consisting of: H, C1_8alkyl, cycloalkyl, aryl, heterocycle, arylCl_8alkyl;
R5 is chosen in the group consisting of: H, C1_8alkyl, C00R. CN, aryl.
heterocycle;
X is chosen in the group consisting of: 0, C(=0)R, COOR, N02, CONR'R
wherein R and R' are as above defined;
Q is chosen in the group consisting of: Single bond. C1_8alkyl, C~_ $alkenyl. CZ_$alkinyl, cycloalkyl, C0, CONK, NR, wherein R is as above defined;
W is chosen in the group consisting of: H. CI_aalkyl. CZ_$alkenyl. C2_ 8alkinyl, cycloalkyl, trifluoromethyl, C1_8alkoxy. C1_8alkoxy-C1_ 8alkyl, arylCl-8alkyl, aryl, aryloxy, arylamino, C1-8alkylcarbonyl, arylcarbonyl, halogen, CN, NRR', C1-8alkylamino, heterocycle wherein the groups alkyl, alkenyl, alkinyl, cycloalkyl, aryl, heterocycle, can be substitued;
n is an integer comprised between 1 and 4;
the symbol - - means that the corresponding bonds a, b, c, d e, f, and g can be S111g12 or double bonds;
with the proviso that when b or f are a double bond then the group R5 is absent; and with the groviso that the following two compounds are excluded: 4-carbonitril-2,3-dihydro-(1H)-benzo[c)quinolizin-3-one and 3,4-dihydro-1-phenyl-4aH-benzo[c]quinolizin-3-one;
their pharmaceutically acceptable salts or esters, their process for preparation and their use as inhibitors of steroid 5alpha-reductases (hereinafter indicated as 5alpha-reductases).
The invention refers also to compounds of formula (4) (4) wherein W, Q, n, R3, R4, R5 are as above defined and Z is a protecting group for the amide-group with the proviso that when R3 = R4 = RS -(wQ)n = H than Z is not a group ethoxycarbonyl.
State of the art The enzyme known as steroid 5alpha-reductase is a system formed by two iso-enzymes (type I and type II or SalphaR-I and 5alphaR-II
respectively)) which converts testosterone into dihydrotestosterone, -- , t . '.
,_ - . .
- 2a -the most powerful androgen circulating in the body.
The type I iso-enzyme (5alphaR-I) is mainly present in liver and skin while the type II iso-enzyme (5alphaR-II) is mainly present in the prostate tissue and in the male sexual organs and its activity is essential in the fetal developping process for the differentiation of the external sexual organs.
The production of dihydrotestosterone is associated with some pathologies which are widely diffused as for example benign prostate hypertrophy, prostate cancer, baldness and acne in men and hirsutism in women. More particularly iso-enzyme I plays a role in the pathologies regarding the skin while iso-enzyme-II is involved in Alv~~igCD j~~
W O 97129107 PCT/EF~97100552 prostate pathologies.
._ . _ In the recent years a lot of international searchers have tried to isolate new compounds capable of inhibiting the 5a-reductase enzyme in order to treat the above said pathologies, especially, if possible, acting selectively on only one of the two iso-enzymes.
Inhibitors of 5a-reductase, and also of the iso-enzymes 5aR-I and 5aR-II were already described, for example finasteride used with success in the treatment of benign prostate hypertrophy [see for example J.Med.Chem. 36, x+313-15 (19g3), J.Med.Chem. 3'7, 3871-'74 (1994)]. It is ZO therefore evident the importance of developing new compounds capable of inhibiting the action of the 5a-reductase enzyme and in particular capable of acting selectively on 5oR-I iso-enzyme which, as said, is responsible, of widely diffused pathologies having an high impact as baldness in men and hirsutism in women.
Detailed description of the invention The present invention refers to new compounds capable of inhibiting the 5a-reductase enzyme, either selectively in respect of 5aR-I and 5aR-II or on both the iso-enzymes, useful for the treatment of the pathologies mediated by the enzyme.
The-products according to the invention have general formula (I) (I) RZ ~'3 wherein the substituents R1, R2, R3, R4, R5, R6, X, Q, W, n and the symbol ----- are as above defined.
According to the present invention with group C1_8alkyl. C2_8alkenyl and C2_8alkinyl are indicated linear or branched alkyl radicals as for example: methyl, ethyl, propyl, isopropyl, butyl, pentyl,_ hexyl,, heptyl, octyl, ethylene, propene, butene, isobutene, acetylene, propine , butine etC.
''v~ith cycloalkyl are indicated: cyclopropane, cyclobutane.
~~yclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camphane, adamantane.
With aryl are indicated: phenyl and tlaphthyl.
Heterocycle means in particular: saturated or aromatic heterocycles containing one or more N atoms, more particularly: piridine, i.midazole, pyrrole. indole, triazoles, pyrrolidine, piperidine, ~falogen means: fluorine, chlorine, bromine, iodine.
T'he substituents of the above said group W are preferably: halogen, OR, phenyl. NRR', CN, COOR. CONRR', C1_8alkyl (wherein R and R' are as above defined).
In particular, according to the present invention compounds of formula (I) are preferred wherein:
R5 = H, heterocycle X = 0 Q = single bond. C0, CONR. NR (wherein R is as above defined) W - H, F, C1, Br, Me, t-butyl, C1_$alkoxy, 2,5-dimethylhexyl, t:~ifluoromethyl. 2,5-(di-trifluoromethyl)-phenyl, 4-methoxy-phenyl. 4-f:Luoro-phenyl, phenyl, phenyl-C1_8alkyl, Cl-$alkylcarbonyl, phenylcarbonyl .
WO 97129107 PCT/EP'97/00552 n = 1 and 2 ' Rl. R2, R3, R4, R6 = H, Me, CN, phenyl, COOR, CONRR' (wherein R and R' are as above defined).
Among the pharmaceutically acceptable esters and salts according to the present invention the following can be mentioned: hydrochloride, sulphate, citrate, formiate, phosphate.
Preferred compounds according to the present invention are:
1,2,4,4a,5,6 hexahydro-(11H)-benzo[c]quinolizine-3-one;
8-chloro-1,2,4,4a,5,6 hexahydro-(11H)-benzo[c]quinolizine-3-one;
1,2,4,4a,5,6 hexahydro-8-methyl-(11H)-benzo[c]quinolizine-3-one;
1,2,4,4a,5,6 hexahydro-4-methyl-(11H)-benzo[c]quinolizine-3-one;
1,2,4,4a,5,6 hexahydro-1-methyl-(11H)-benzo[c]quinolizine-3-one;
1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
8-chloro-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
8-methyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4-methyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
1-methyl-1,2,5,6 tetrahydro-(12H)-benzo[c]quinolizine-3-one;
4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
Field of the invention The present invention refers to benzo[c]quinolizine derivatives of general formula (I) R' ~~-SnW)n i: ~,~ (I) ~' a g a b .1 ~f ~ ,.
''d T ! T
z Rs wherein:
R1, R2, R3, R4, R6, same or different, are chosen in the group consisting of: H, C1_$alkyl. C2_$alkenyl, CZ_8alkiny7., cycloalkyl, aryl, heterocycle, halogen, CN, azide. NRR', C1_$alkylamino, arylamino, C1_$alkyloxy, aryloxy, C00R, GONRR' wherein R and R', same or different, are chosen in the group consisting of: H, C1_8alkyl, cycloalkyl, aryl, heterocycle, arylCl_8alkyl;
R5 is chosen in the group consisting of: H, C1_8alkyl, C00R. CN, aryl.
heterocycle;
X is chosen in the group consisting of: 0, C(=0)R, COOR, N02, CONR'R
wherein R and R' are as above defined;
Q is chosen in the group consisting of: Single bond. C1_8alkyl, C~_ $alkenyl. CZ_$alkinyl, cycloalkyl, C0, CONK, NR, wherein R is as above defined;
W is chosen in the group consisting of: H. CI_aalkyl. CZ_$alkenyl. C2_ 8alkinyl, cycloalkyl, trifluoromethyl, C1_8alkoxy. C1_8alkoxy-C1_ 8alkyl, arylCl-8alkyl, aryl, aryloxy, arylamino, C1-8alkylcarbonyl, arylcarbonyl, halogen, CN, NRR', C1-8alkylamino, heterocycle wherein the groups alkyl, alkenyl, alkinyl, cycloalkyl, aryl, heterocycle, can be substitued;
n is an integer comprised between 1 and 4;
the symbol - - means that the corresponding bonds a, b, c, d e, f, and g can be S111g12 or double bonds;
with the proviso that when b or f are a double bond then the group R5 is absent; and with the groviso that the following two compounds are excluded: 4-carbonitril-2,3-dihydro-(1H)-benzo[c)quinolizin-3-one and 3,4-dihydro-1-phenyl-4aH-benzo[c]quinolizin-3-one;
their pharmaceutically acceptable salts or esters, their process for preparation and their use as inhibitors of steroid 5alpha-reductases (hereinafter indicated as 5alpha-reductases).
The invention refers also to compounds of formula (4) (4) wherein W, Q, n, R3, R4, R5 are as above defined and Z is a protecting group for the amide-group with the proviso that when R3 = R4 = RS -(wQ)n = H than Z is not a group ethoxycarbonyl.
State of the art The enzyme known as steroid 5alpha-reductase is a system formed by two iso-enzymes (type I and type II or SalphaR-I and 5alphaR-II
respectively)) which converts testosterone into dihydrotestosterone, -- , t . '.
,_ - . .
- 2a -the most powerful androgen circulating in the body.
The type I iso-enzyme (5alphaR-I) is mainly present in liver and skin while the type II iso-enzyme (5alphaR-II) is mainly present in the prostate tissue and in the male sexual organs and its activity is essential in the fetal developping process for the differentiation of the external sexual organs.
The production of dihydrotestosterone is associated with some pathologies which are widely diffused as for example benign prostate hypertrophy, prostate cancer, baldness and acne in men and hirsutism in women. More particularly iso-enzyme I plays a role in the pathologies regarding the skin while iso-enzyme-II is involved in Alv~~igCD j~~
W O 97129107 PCT/EF~97100552 prostate pathologies.
._ . _ In the recent years a lot of international searchers have tried to isolate new compounds capable of inhibiting the 5a-reductase enzyme in order to treat the above said pathologies, especially, if possible, acting selectively on only one of the two iso-enzymes.
Inhibitors of 5a-reductase, and also of the iso-enzymes 5aR-I and 5aR-II were already described, for example finasteride used with success in the treatment of benign prostate hypertrophy [see for example J.Med.Chem. 36, x+313-15 (19g3), J.Med.Chem. 3'7, 3871-'74 (1994)]. It is ZO therefore evident the importance of developing new compounds capable of inhibiting the action of the 5a-reductase enzyme and in particular capable of acting selectively on 5oR-I iso-enzyme which, as said, is responsible, of widely diffused pathologies having an high impact as baldness in men and hirsutism in women.
Detailed description of the invention The present invention refers to new compounds capable of inhibiting the 5a-reductase enzyme, either selectively in respect of 5aR-I and 5aR-II or on both the iso-enzymes, useful for the treatment of the pathologies mediated by the enzyme.
The-products according to the invention have general formula (I) (I) RZ ~'3 wherein the substituents R1, R2, R3, R4, R5, R6, X, Q, W, n and the symbol ----- are as above defined.
According to the present invention with group C1_8alkyl. C2_8alkenyl and C2_8alkinyl are indicated linear or branched alkyl radicals as for example: methyl, ethyl, propyl, isopropyl, butyl, pentyl,_ hexyl,, heptyl, octyl, ethylene, propene, butene, isobutene, acetylene, propine , butine etC.
''v~ith cycloalkyl are indicated: cyclopropane, cyclobutane.
~~yclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camphane, adamantane.
With aryl are indicated: phenyl and tlaphthyl.
Heterocycle means in particular: saturated or aromatic heterocycles containing one or more N atoms, more particularly: piridine, i.midazole, pyrrole. indole, triazoles, pyrrolidine, piperidine, ~falogen means: fluorine, chlorine, bromine, iodine.
T'he substituents of the above said group W are preferably: halogen, OR, phenyl. NRR', CN, COOR. CONRR', C1_8alkyl (wherein R and R' are as above defined).
In particular, according to the present invention compounds of formula (I) are preferred wherein:
R5 = H, heterocycle X = 0 Q = single bond. C0, CONR. NR (wherein R is as above defined) W - H, F, C1, Br, Me, t-butyl, C1_$alkoxy, 2,5-dimethylhexyl, t:~ifluoromethyl. 2,5-(di-trifluoromethyl)-phenyl, 4-methoxy-phenyl. 4-f:Luoro-phenyl, phenyl, phenyl-C1_8alkyl, Cl-$alkylcarbonyl, phenylcarbonyl .
WO 97129107 PCT/EP'97/00552 n = 1 and 2 ' Rl. R2, R3, R4, R6 = H, Me, CN, phenyl, COOR, CONRR' (wherein R and R' are as above defined).
Among the pharmaceutically acceptable esters and salts according to the present invention the following can be mentioned: hydrochloride, sulphate, citrate, formiate, phosphate.
Preferred compounds according to the present invention are:
1,2,4,4a,5,6 hexahydro-(11H)-benzo[c]quinolizine-3-one;
8-chloro-1,2,4,4a,5,6 hexahydro-(11H)-benzo[c]quinolizine-3-one;
1,2,4,4a,5,6 hexahydro-8-methyl-(11H)-benzo[c]quinolizine-3-one;
1,2,4,4a,5,6 hexahydro-4-methyl-(11H)-benzo[c]quinolizine-3-one;
1,2,4,4a,5,6 hexahydro-1-methyl-(11H)-benzo[c]quinolizine-3-one;
1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
8-chloro-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
8-methyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4-methyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
1-methyl-1,2,5,6 tetrahydro-(12H)-benzo[c]quinolizine-3-one;
4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
5,6-dihydro-(11H)-benzo[c]quinolizine-3-one;
8-chloro-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
8-chloro-1-methyl-4,4a,5,6-tetrahydro-(11H)-benzo[c]quinolizine-3-one;
8-methyl-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4-methyl-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one (cis) and (trans);
t 8-chloro-4-methyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4,8-dimethyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4,8-dimethyl-4.4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one (cis) and (trans);
8-chloro-4-methyl-4,4a,5,6-tetrahydro-(11H)-benzo[c]quinolizine-3-one (cis) and (trans).
The compounds according to the present invention can be prepared for example starting from compounds of formula 2 (WQ~n ~ ( 2 ) N' '_O
H
(2}
wherein R3, R~, W, Q and n are as above defined, following the reaction Scheme reported hereinafter.
The compounds 2 are commercialy available or can be prepared according to known techniques.
As it can be seen from the Scheme the preparation of the compounds according to the invention involves the protection of the amide-group in compound 2 by the protecting group Z, for example tert-butoxycarbonyl (t-Boc), to give compound 3; compound 3 is reduced to compound 4, for example (when R5 is H) with sodium borohydride in ethanol (pH 3), which is reacted with a silylether 6, produced "in situ" starting from vinyl-ketones 5 (wherein R1, R2 and R6 are as above defined) with a silylating agent as trimethylsilyltrifluorometansulphonic anhydride (TMSOTf) and thereafter hydrolized, for example in sodium hydrogencarbonate, to give the compounds of formula ( I ) wherein X - 0 . The possible introduction of the double bonds and the transformation of the group X
WO 97!29107 PCT/EF97/00552 _ 7 _ in one of the other groups mentioned above can be easily performed according to known techniques starting from the corresponding compound of formula (I) obtained as indicated. For example the introduction of the double bonds in position a or b, can be performed by reaction of dichlorodicyanoquinone (DDQ) with the corresponding silylenolethers or by oxidation with mercuric acetate of the saturated corresponding compound obtained as described above. The transformation of group X
can be performed via the corresponding enoltriflates and their carbonylation in the presence of palladium diacetate, triphenylphosphine and the suitable nucleophilic reagent (alcohol, amine, nitro-group).
Example 1 Preparation of N-(t-butoxycarbonyl)-3,4-dihydroguinolin-2(1H) one [compound 3 wherein (QW)n = H, R3 = R4 = H]
5 g (34 mmoles) of 3,4-dihydroquinolin-2(1H)-one [compound 2 wherein (QW)2 - H, R3 - R4 - H] and 111 ml of CH2C12 are charged, under nitrogen, in a 250 ml round bottom flask, equipped with magnetic stirrer.
To the above said mixture 4.7 ml (34 mmoles) of triethylamine (distilled on KOH), 8.9 g (40.8 mmoles) of di-butyl dicarbonate and 1 g (8.2 mmoles) of 4-dimethylaminopyridine are added. The mixture is stirred under reflux for 5 h, then for one night at room temperature and thereafter the solvent is removed and 200 ml of water are added.
The aqueous phase is extracted with diethylether and the organic phase is neutralized with an aqueous solution of KHS04 (1 M). The organic phase is washed with a saturated solution of NaCl and dried on Na2S04.
After filtration and removal of the solvent 8.23 g of the desired product are obtained (white crystals). M.p.: 68 - 69°C. Yield: 98%.
Example 2 Preparation of N-(t-butox carbonyl)-2-ethox -1 2 3 4-tetrahydroquinoline [compound 4 wherein (QW)n = H, R3 = R4 = R5 = H].
4.35 g (17.6 mmoles) of the compound obtained from example 1 and 136 ml of absolute ethanol are charged in a 500 ml .round bottom flask equipped with magnetic stirrer.
The solution is cooled at -25°C and 2.66 g (70.4.mmoles} of NaBH4 (subdivided in 6 portions) are added to the mixture in 1 h. After 4 h ZO a solution of HCl 2N in absolute ethanol is added to the mixture, up to pH 3, and the mixture is stirred at 0°C for 1,5 h. 100 ml of water are added, the aqueous phase is extracted with methylene chloride, the organic phase is washed with a saturated solution of NaHC03 and a saturated solution of NaCl and the mixture is dried on _Na2S04. After filtration the solvent is removed and 4,74 g of the expected product are obtained (dense yellow liquid); yield g6%.
Operating as above said other compounds 4 wherein the substituents can not be reduced by NaBH4 are obtained; if substituents which could be reduced by NaBH~ are present these must be previously protected.
Example 3 Preparation of 1.2.4.~a.5,6-hexahvdro-(11H)-benzo~cl4uinolizin-3-one [compound of formula (I) wherein X = 0; (QW)n = H; R1 = R2 = R3 = R4 =
R5 = R6 = H; a.b,c.e,f,g = Single bond]
70 ul (0.86 mmoles) of 3-buten-2-one [compound of formula 5 wherein R1 - RZ = R6 = H] and 2 ml of anhydrous CH2C12 are charged, at 0°C under argon in a two-necked round bottom flask equipped with magnetic stirrer and dropping funnel.
1'70 ul (1.22 mmoles) of triethylamine (distilled on KOH) and 209 ul (1.08 mmoles) of trimethylsilyltrifluorometansulphonate (TMDOTf) (drop by drop) are added to the mixture. In this conditions 2-' (trimethylsilyloxy}-1,3-butadiene [compound 6 wherein R1 = R2 = R6 =
H] is formed "in situ". The mixture is stirred for 45 minutes and thereafter a solution of 100 mg (0.36 mmoles} of the product from Example 2 in 2 mI of anhydrous CH2Ci2 is added therein, drop by drop, together with 69ul (0.36 mmoles) of TMSOTf. The mixture is brought to room temperature and after 30 minutes 4 ml of a saturated solution of NaHC03 are added and the mixture is stirred vigorously for 36 h.
4 ml of water are added to the mixture and the aqueous phase is extracted with methylene chloride, the organic phase is washed with a saturated solution of NaHC03, water, a saturated solution of NaCl and is dried on Na2S04. After filtration the solvent is removed and 5g mg of crude product are obtained. The product is purified by flash chromatography on silica gel column (FCC) eluting with methylene chloride and triethylamine 10. 18 mg of the wanted product are obtained (crystals). M.p.: 53 - 54C. Yield 25%.
Using various vinyl-ketones 5, or using directly the various silylenolethers 6 (when available), it is possible to prepare the corresponding derivatives of formula (I).
In particular when I-methoxy-3-(trimethylsilyloxy)-1-3-butadiene (compound 6 wherein R1 - MeO, R2 = H, R6 = H) was used, 4,4a,5,6-- tetrahydro-(11H)-benzo[c]quinolizin-3-one (compound I wherein X = 0, (QW)n = H, R1 = R2 = R3 = R4 = R5 = R6 = H, a = double bond;
b,c,e,f,g - single bond] was directly obtained according to the synthesis described in the following Example 4.
Example 4 Preparation of 4,4a,5,6-tetrahydro-(lIH)-benzo[c]quinolizin-3-one [compound I wherein X = 0. (QWjn = H; R1 = R2 = R3 = R4 = R5 = R6 = H;
a = double bond; b.c.e,f,g = single bond].
To a stirred solution of compound 4 [ (QW)n = H. R3 = R4 = H] (4 g.
14.42 mmolj of the example 3, in 75 ml of anhydrous CH2C12 under argon at -10°C is added, dropwise in 7 min, 28.84 ml of a 1M solution of TiCl4 in CH2C12 maintaining the temperature heloca -5°C.~Then 1-methoxy-3-(trimethylsilyloxyj-1-3-butadiene. (compound 6. R1 = MeO, R2 = H. R6 = H) (3.29 ml, 17.3 mmol) is added by syringe at 0°C, and the reaction was left aside at room temperature for 1 h. The reaction mixture is added, cautiously, with 100 ml of NaHC03 satured solution, and then stirred for 30 min. The organic layer is separated, washed with water, filtered on Celite and dried over Na2S04. After removal of the solvent the crude product is purified by flash column chromatography (eluant light-petroleum ether/ethyl acetate 1:4) affording 0.72 g (25~ yield) of the expected product (white crystals.
m.p.: 135-137°C).
Example 5 a)- Preparation of 4-methyl-4.4a.5,6-tetrahydro-(11H)-benzo~clquinolizine-3-one [compound of formula (I) wherein X - 0;
(QW)n = H; RI = R3 = R4 = R5 = R6 = H; RZ = Me; a = double bond;
b.c.e,f,g - single bonds], 4 methyl-1.2,5.6-tetrahydro-(11H)-benzo[c]quinolizine-3-one [compound of formula (I) wherein X - 0;
(QW)n = H; R1 = R3 = R4 = R6 = H; R2 = Me; b = double bond; a.c,e.f,g - single bonds] and 4-methyl-5.6-dihydro-(11H)-benzo[c]quinolizine-3-one [compound of formula (Ij wherein X = 0; (QW)2 = H; R1 = R3 = R4 =
WD 97129107 PCTlEF97lOD552 R6 = H; R2 = Me; a,b = double bonds; c.e,f,g = single bonds .
._ . _ 1 g (4.64 mmol) of 4-methyl-1,2,4,4a,5,6-hexahydro-(11H)-benzo[c]quinolizine-3-one [compound of formula (I) whe i X
, re n - 0;
(QW)n = H; R1 = R3 = R4 = R5 = R6 = H; R2 = Me; a,b,c,e,f,g = single bonds, obtained according to example 3 by reaction of compound (wherein - -(QW)n H~ R3 R4 - R
- H) of exam l p e and ethylvinylketone (compound 5 wherein R
= R
= H; R
= M
) d 12 e an 0 ml of 5% solution (v/v) of glacial acetic acid in water are charged under nitrogen in a two-necked round bottom flask, equipped with magnetic stirrer, refrigerator and dropping funnel. Under vigorous stirring, 727 g (18-56 mmol) of tetrasodic salt EDTA and 5.92 g (18.56 mmol) of (CH3C02)2Hg are added and the reaction mixture is heated at 90C for 2h. After cooling at room temperature the reaction mixture is added with 120 ml of water and extracted with methylene chloride (4x70 ml).
The separated organic phase is washed with a satured solution of NaHC03, with a satured solution of NaCl then dried over Na2S04.
After removal of the solvent the crude product is purified by flash chromatography on silica gel by elution with ethylacetate/light petroleum ether 2:1 affording:
83- mg (10%) (gummy solid) of cis-4-methyl-4,4a,5,6-tetrahydro-(11H)-benzo[c]quinolizine-3-one [compound of formula (I) wherein X - 0;
(QW)n = H; R1 - R3 = R4 = R5 = R6 = H; R2 = Me; a = double bond;
b,c,e,f,g = single bonds]
350 mg (40%) (crystals, m.p.. 148-150C) of 4 methyl-2,2,5,6-tetrahydro-(11H)-benzo[c]quinolizine-3-one [compound of formula (I) wherein X = 0; (QW)n = H; R1 = R3 = R4 = R6 = H; R2 = Me;
b = double bond; a,c,e,f,g = single bonds] and 107 mg (12%) (gummy solid) of 4-methyl-5,6-dihydro-(11H)-_ benzo[c]quinolizine-3-one [compound of formula (I) wherein X - 0;
(QW)n = H; R1 = R3 = R4 = R6 = H; R2 = Me; a,b=double bonds; c,e,f,g =
single bonds].
Activity Test The inhibition potency of the prepared compounds in respect of the iso-enzymes 1 and 2 of 5a-reductase was determined using tissue samples (for example prostate human tissue) or human cellular systems (for example DU 145 cells) expressing iso-enzymes 2 and 1 respectively.
The samples are incubated in the presence of testosterone labelled with tritium and thereafter the quantity of labelled dihydrotestosterone formed in the absence and in the presence of the inhibitor is measured.
The compounds showed high inhibiting power of 5a-reductase enzyme (in particular of iso-enzyme 1) with an inhibition higher than 50% at the concentration of 10 - 100 nM.
For the therapeuticaladministration the compounds according to the invention are prepared in the form of pharmaceutical compositions containing the active principle and the organic or inorganic excipients suitable for the oral, parenteral or topic administration of the compositions. The pharmaceutical compositions can thererfore be in the solid form (dragees, suppositories, creams, ointments), liquid form (solutions, suspensions, emulsions) and can possibly contain the stabilizers, conservatives, humectants, emulsifier, buffers or salts used for equilibrating the osmotic pressure which are commonly used in ' the art.
Generally the administration of the compounds is performed according ._ . _ to the modalities and quantities observed for the known agents used ' for the same purposes and taking into consideration the age and conditions of the patients.
~, .. , . . E ".; ~ r, (' ~~,'t,~
8-chloro-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
8-chloro-1-methyl-4,4a,5,6-tetrahydro-(11H)-benzo[c]quinolizine-3-one;
8-methyl-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4-methyl-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one (cis) and (trans);
t 8-chloro-4-methyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4,8-dimethyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4,8-dimethyl-4.4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one (cis) and (trans);
8-chloro-4-methyl-4,4a,5,6-tetrahydro-(11H)-benzo[c]quinolizine-3-one (cis) and (trans).
The compounds according to the present invention can be prepared for example starting from compounds of formula 2 (WQ~n ~ ( 2 ) N' '_O
H
(2}
wherein R3, R~, W, Q and n are as above defined, following the reaction Scheme reported hereinafter.
The compounds 2 are commercialy available or can be prepared according to known techniques.
As it can be seen from the Scheme the preparation of the compounds according to the invention involves the protection of the amide-group in compound 2 by the protecting group Z, for example tert-butoxycarbonyl (t-Boc), to give compound 3; compound 3 is reduced to compound 4, for example (when R5 is H) with sodium borohydride in ethanol (pH 3), which is reacted with a silylether 6, produced "in situ" starting from vinyl-ketones 5 (wherein R1, R2 and R6 are as above defined) with a silylating agent as trimethylsilyltrifluorometansulphonic anhydride (TMSOTf) and thereafter hydrolized, for example in sodium hydrogencarbonate, to give the compounds of formula ( I ) wherein X - 0 . The possible introduction of the double bonds and the transformation of the group X
WO 97!29107 PCT/EF97/00552 _ 7 _ in one of the other groups mentioned above can be easily performed according to known techniques starting from the corresponding compound of formula (I) obtained as indicated. For example the introduction of the double bonds in position a or b, can be performed by reaction of dichlorodicyanoquinone (DDQ) with the corresponding silylenolethers or by oxidation with mercuric acetate of the saturated corresponding compound obtained as described above. The transformation of group X
can be performed via the corresponding enoltriflates and their carbonylation in the presence of palladium diacetate, triphenylphosphine and the suitable nucleophilic reagent (alcohol, amine, nitro-group).
Example 1 Preparation of N-(t-butoxycarbonyl)-3,4-dihydroguinolin-2(1H) one [compound 3 wherein (QW)n = H, R3 = R4 = H]
5 g (34 mmoles) of 3,4-dihydroquinolin-2(1H)-one [compound 2 wherein (QW)2 - H, R3 - R4 - H] and 111 ml of CH2C12 are charged, under nitrogen, in a 250 ml round bottom flask, equipped with magnetic stirrer.
To the above said mixture 4.7 ml (34 mmoles) of triethylamine (distilled on KOH), 8.9 g (40.8 mmoles) of di-butyl dicarbonate and 1 g (8.2 mmoles) of 4-dimethylaminopyridine are added. The mixture is stirred under reflux for 5 h, then for one night at room temperature and thereafter the solvent is removed and 200 ml of water are added.
The aqueous phase is extracted with diethylether and the organic phase is neutralized with an aqueous solution of KHS04 (1 M). The organic phase is washed with a saturated solution of NaCl and dried on Na2S04.
After filtration and removal of the solvent 8.23 g of the desired product are obtained (white crystals). M.p.: 68 - 69°C. Yield: 98%.
Example 2 Preparation of N-(t-butox carbonyl)-2-ethox -1 2 3 4-tetrahydroquinoline [compound 4 wherein (QW)n = H, R3 = R4 = R5 = H].
4.35 g (17.6 mmoles) of the compound obtained from example 1 and 136 ml of absolute ethanol are charged in a 500 ml .round bottom flask equipped with magnetic stirrer.
The solution is cooled at -25°C and 2.66 g (70.4.mmoles} of NaBH4 (subdivided in 6 portions) are added to the mixture in 1 h. After 4 h ZO a solution of HCl 2N in absolute ethanol is added to the mixture, up to pH 3, and the mixture is stirred at 0°C for 1,5 h. 100 ml of water are added, the aqueous phase is extracted with methylene chloride, the organic phase is washed with a saturated solution of NaHC03 and a saturated solution of NaCl and the mixture is dried on _Na2S04. After filtration the solvent is removed and 4,74 g of the expected product are obtained (dense yellow liquid); yield g6%.
Operating as above said other compounds 4 wherein the substituents can not be reduced by NaBH4 are obtained; if substituents which could be reduced by NaBH~ are present these must be previously protected.
Example 3 Preparation of 1.2.4.~a.5,6-hexahvdro-(11H)-benzo~cl4uinolizin-3-one [compound of formula (I) wherein X = 0; (QW)n = H; R1 = R2 = R3 = R4 =
R5 = R6 = H; a.b,c.e,f,g = Single bond]
70 ul (0.86 mmoles) of 3-buten-2-one [compound of formula 5 wherein R1 - RZ = R6 = H] and 2 ml of anhydrous CH2C12 are charged, at 0°C under argon in a two-necked round bottom flask equipped with magnetic stirrer and dropping funnel.
1'70 ul (1.22 mmoles) of triethylamine (distilled on KOH) and 209 ul (1.08 mmoles) of trimethylsilyltrifluorometansulphonate (TMDOTf) (drop by drop) are added to the mixture. In this conditions 2-' (trimethylsilyloxy}-1,3-butadiene [compound 6 wherein R1 = R2 = R6 =
H] is formed "in situ". The mixture is stirred for 45 minutes and thereafter a solution of 100 mg (0.36 mmoles} of the product from Example 2 in 2 mI of anhydrous CH2Ci2 is added therein, drop by drop, together with 69ul (0.36 mmoles) of TMSOTf. The mixture is brought to room temperature and after 30 minutes 4 ml of a saturated solution of NaHC03 are added and the mixture is stirred vigorously for 36 h.
4 ml of water are added to the mixture and the aqueous phase is extracted with methylene chloride, the organic phase is washed with a saturated solution of NaHC03, water, a saturated solution of NaCl and is dried on Na2S04. After filtration the solvent is removed and 5g mg of crude product are obtained. The product is purified by flash chromatography on silica gel column (FCC) eluting with methylene chloride and triethylamine 10. 18 mg of the wanted product are obtained (crystals). M.p.: 53 - 54C. Yield 25%.
Using various vinyl-ketones 5, or using directly the various silylenolethers 6 (when available), it is possible to prepare the corresponding derivatives of formula (I).
In particular when I-methoxy-3-(trimethylsilyloxy)-1-3-butadiene (compound 6 wherein R1 - MeO, R2 = H, R6 = H) was used, 4,4a,5,6-- tetrahydro-(11H)-benzo[c]quinolizin-3-one (compound I wherein X = 0, (QW)n = H, R1 = R2 = R3 = R4 = R5 = R6 = H, a = double bond;
b,c,e,f,g - single bond] was directly obtained according to the synthesis described in the following Example 4.
Example 4 Preparation of 4,4a,5,6-tetrahydro-(lIH)-benzo[c]quinolizin-3-one [compound I wherein X = 0. (QWjn = H; R1 = R2 = R3 = R4 = R5 = R6 = H;
a = double bond; b.c.e,f,g = single bond].
To a stirred solution of compound 4 [ (QW)n = H. R3 = R4 = H] (4 g.
14.42 mmolj of the example 3, in 75 ml of anhydrous CH2C12 under argon at -10°C is added, dropwise in 7 min, 28.84 ml of a 1M solution of TiCl4 in CH2C12 maintaining the temperature heloca -5°C.~Then 1-methoxy-3-(trimethylsilyloxyj-1-3-butadiene. (compound 6. R1 = MeO, R2 = H. R6 = H) (3.29 ml, 17.3 mmol) is added by syringe at 0°C, and the reaction was left aside at room temperature for 1 h. The reaction mixture is added, cautiously, with 100 ml of NaHC03 satured solution, and then stirred for 30 min. The organic layer is separated, washed with water, filtered on Celite and dried over Na2S04. After removal of the solvent the crude product is purified by flash column chromatography (eluant light-petroleum ether/ethyl acetate 1:4) affording 0.72 g (25~ yield) of the expected product (white crystals.
m.p.: 135-137°C).
Example 5 a)- Preparation of 4-methyl-4.4a.5,6-tetrahydro-(11H)-benzo~clquinolizine-3-one [compound of formula (I) wherein X - 0;
(QW)n = H; RI = R3 = R4 = R5 = R6 = H; RZ = Me; a = double bond;
b.c.e,f,g - single bonds], 4 methyl-1.2,5.6-tetrahydro-(11H)-benzo[c]quinolizine-3-one [compound of formula (I) wherein X - 0;
(QW)n = H; R1 = R3 = R4 = R6 = H; R2 = Me; b = double bond; a.c,e.f,g - single bonds] and 4-methyl-5.6-dihydro-(11H)-benzo[c]quinolizine-3-one [compound of formula (Ij wherein X = 0; (QW)2 = H; R1 = R3 = R4 =
WD 97129107 PCTlEF97lOD552 R6 = H; R2 = Me; a,b = double bonds; c.e,f,g = single bonds .
._ . _ 1 g (4.64 mmol) of 4-methyl-1,2,4,4a,5,6-hexahydro-(11H)-benzo[c]quinolizine-3-one [compound of formula (I) whe i X
, re n - 0;
(QW)n = H; R1 = R3 = R4 = R5 = R6 = H; R2 = Me; a,b,c,e,f,g = single bonds, obtained according to example 3 by reaction of compound (wherein - -(QW)n H~ R3 R4 - R
- H) of exam l p e and ethylvinylketone (compound 5 wherein R
= R
= H; R
= M
) d 12 e an 0 ml of 5% solution (v/v) of glacial acetic acid in water are charged under nitrogen in a two-necked round bottom flask, equipped with magnetic stirrer, refrigerator and dropping funnel. Under vigorous stirring, 727 g (18-56 mmol) of tetrasodic salt EDTA and 5.92 g (18.56 mmol) of (CH3C02)2Hg are added and the reaction mixture is heated at 90C for 2h. After cooling at room temperature the reaction mixture is added with 120 ml of water and extracted with methylene chloride (4x70 ml).
The separated organic phase is washed with a satured solution of NaHC03, with a satured solution of NaCl then dried over Na2S04.
After removal of the solvent the crude product is purified by flash chromatography on silica gel by elution with ethylacetate/light petroleum ether 2:1 affording:
83- mg (10%) (gummy solid) of cis-4-methyl-4,4a,5,6-tetrahydro-(11H)-benzo[c]quinolizine-3-one [compound of formula (I) wherein X - 0;
(QW)n = H; R1 - R3 = R4 = R5 = R6 = H; R2 = Me; a = double bond;
b,c,e,f,g = single bonds]
350 mg (40%) (crystals, m.p.. 148-150C) of 4 methyl-2,2,5,6-tetrahydro-(11H)-benzo[c]quinolizine-3-one [compound of formula (I) wherein X = 0; (QW)n = H; R1 = R3 = R4 = R6 = H; R2 = Me;
b = double bond; a,c,e,f,g = single bonds] and 107 mg (12%) (gummy solid) of 4-methyl-5,6-dihydro-(11H)-_ benzo[c]quinolizine-3-one [compound of formula (I) wherein X - 0;
(QW)n = H; R1 = R3 = R4 = R6 = H; R2 = Me; a,b=double bonds; c,e,f,g =
single bonds].
Activity Test The inhibition potency of the prepared compounds in respect of the iso-enzymes 1 and 2 of 5a-reductase was determined using tissue samples (for example prostate human tissue) or human cellular systems (for example DU 145 cells) expressing iso-enzymes 2 and 1 respectively.
The samples are incubated in the presence of testosterone labelled with tritium and thereafter the quantity of labelled dihydrotestosterone formed in the absence and in the presence of the inhibitor is measured.
The compounds showed high inhibiting power of 5a-reductase enzyme (in particular of iso-enzyme 1) with an inhibition higher than 50% at the concentration of 10 - 100 nM.
For the therapeuticaladministration the compounds according to the invention are prepared in the form of pharmaceutical compositions containing the active principle and the organic or inorganic excipients suitable for the oral, parenteral or topic administration of the compositions. The pharmaceutical compositions can thererfore be in the solid form (dragees, suppositories, creams, ointments), liquid form (solutions, suspensions, emulsions) and can possibly contain the stabilizers, conservatives, humectants, emulsifier, buffers or salts used for equilibrating the osmotic pressure which are commonly used in ' the art.
Generally the administration of the compounds is performed according ._ . _ to the modalities and quantities observed for the known agents used ' for the same purposes and taking into consideration the age and conditions of the patients.
~, .. , . . E ".; ~ r, (' ~~,'t,~
Claims (10)
1. Benzo[c]-quinolizine compounds of formula (I) wherein:
R1, R2, R3, R4, R5, same or different, are chosen in the group consisting of:
H, C1-8alkyl, C2-8alkenyl, C2-8alkinyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camphane, adamantane, phenyl, naphthyl, pyridine, imidazole, pyrrole, indole, triazole, pyrrolidine, piperidine, halogen, CN, azide, NRR', C1-8alkylamino, phenylamino, naphthylamino, C1-8alkyloxy, phenyloxy, naphthyloxy, COOR, CONRR' wherein R and R', same or different, are chosen in the group consisting of: H, C1-8alkyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclo-octane, norbornane, camphane, adamantane, phenyl, naphthyl, pyridine, imidazole, pyrrole, indole, triazole, pyrrolidine, piperidine, phenylC1-8alkyl, naphthylC1-8alkyl;
R5 is chosen in the group consisting of: H, C1-8alkyl, COOR, CN, phenyl, naphthyl, pyridine, imidazole, pyrrole, indole, triazole, pyrrolidine, piperidine;
X is chosen in the group consisting of: O, C(=O)R, COOR, NO2, CONR'R
wherein R and R' are as above defined;
Q is chosen in the group consisting of: single bond, C1-8alkyl, C2-8alkenyl, C2-8alkinyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclo-heptane, cyclooctane, norbornane, camphane, adamantane, CO, CONR, NR, wherein R is as above defined;
W is chosen in the group consisting of: H, C1-8alkyl, C2-8alkenyl, C2-8alkinyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camphane, adamantane, trifluoromethyl, C1-8alkoxy, C1-8alkoxy-C1-8alkyl, phenylC1-8alkyl, naphthylC1-8alkyl, phenyl, naphthyl, phenyloxy, naphthyloxy, phenylamino, naphthylamino, C1-8alkylcarbonyl, phenylcarbonyl, naphthylcarbonyl, halogen, CN, NRR', C1-8alkylamino, pyridine, imidazole, pyrrole, indole, triazole, pyrrolidine, piperidine, wherein the groups alkyl, alkenyl, alkinyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camphane, adamantane, phenyl, naphthyl, pyridine, imidazole, pyrrole, indole, triazole, pyrrolidine, piperidine can be substituted by halogen, OR, phenyl, NRR', CN, COOR, CONRR', C1-8alkyl (wherein R and R' are as above defined);
n is an integer comprised between 1 and 4;
the symbol means that the corresponding bonds a, b, c, d e, f, and g can be single or double bonds; and their pharmaceutically acceptable salts or esters;
with the proviso that when b or f are a double bond then the group R5 is absent; and with the proviso that the following compounds are excluded from the claim: 4-carbonitril-2,3-dihydro-(1H)-benzo[c]quinolizin-3-one, 3,4-dihydro-1-phenyl-4aH-benzo[c]quinolizin-3-one,
R1, R2, R3, R4, R5, same or different, are chosen in the group consisting of:
H, C1-8alkyl, C2-8alkenyl, C2-8alkinyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camphane, adamantane, phenyl, naphthyl, pyridine, imidazole, pyrrole, indole, triazole, pyrrolidine, piperidine, halogen, CN, azide, NRR', C1-8alkylamino, phenylamino, naphthylamino, C1-8alkyloxy, phenyloxy, naphthyloxy, COOR, CONRR' wherein R and R', same or different, are chosen in the group consisting of: H, C1-8alkyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclo-octane, norbornane, camphane, adamantane, phenyl, naphthyl, pyridine, imidazole, pyrrole, indole, triazole, pyrrolidine, piperidine, phenylC1-8alkyl, naphthylC1-8alkyl;
R5 is chosen in the group consisting of: H, C1-8alkyl, COOR, CN, phenyl, naphthyl, pyridine, imidazole, pyrrole, indole, triazole, pyrrolidine, piperidine;
X is chosen in the group consisting of: O, C(=O)R, COOR, NO2, CONR'R
wherein R and R' are as above defined;
Q is chosen in the group consisting of: single bond, C1-8alkyl, C2-8alkenyl, C2-8alkinyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclo-heptane, cyclooctane, norbornane, camphane, adamantane, CO, CONR, NR, wherein R is as above defined;
W is chosen in the group consisting of: H, C1-8alkyl, C2-8alkenyl, C2-8alkinyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camphane, adamantane, trifluoromethyl, C1-8alkoxy, C1-8alkoxy-C1-8alkyl, phenylC1-8alkyl, naphthylC1-8alkyl, phenyl, naphthyl, phenyloxy, naphthyloxy, phenylamino, naphthylamino, C1-8alkylcarbonyl, phenylcarbonyl, naphthylcarbonyl, halogen, CN, NRR', C1-8alkylamino, pyridine, imidazole, pyrrole, indole, triazole, pyrrolidine, piperidine, wherein the groups alkyl, alkenyl, alkinyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camphane, adamantane, phenyl, naphthyl, pyridine, imidazole, pyrrole, indole, triazole, pyrrolidine, piperidine can be substituted by halogen, OR, phenyl, NRR', CN, COOR, CONRR', C1-8alkyl (wherein R and R' are as above defined);
n is an integer comprised between 1 and 4;
the symbol means that the corresponding bonds a, b, c, d e, f, and g can be single or double bonds; and their pharmaceutically acceptable salts or esters;
with the proviso that when b or f are a double bond then the group R5 is absent; and with the proviso that the following compounds are excluded from the claim: 4-carbonitril-2,3-dihydro-(1H)-benzo[c]quinolizin-3-one, 3,4-dihydro-1-phenyl-4aH-benzo[c]quinolizin-3-one,
2. Benzo[c]quinolizine compounds of formula (I) according to claim 1 wherein:
R5 = H, pyridine, imidazole, pyrrole, indole, triazole, pyrrolidine, piperidine;
X=O;
Q=single bond, CO, CONR, NR (wherein R is as defined in claim 1);
W=H, F, Cl, Br, Me, t-butyl, C1-8alkoxy, 2,5-dimethylhexyl, trifluoromethyl, 2,5-(di-trifluoromethyl)-phenyl, 4-methoxy-phenyl, 4-fluoro-phenyl, phenyl, phenyl-C1-8alkyl, C1-8alkylcarbonyl, phenylcarbonyl;
n=1 and 2;
R1, R2, R3, R4, R6 =H, Me, CN, phenyl, COOR, CONRR' (wherein R and R' are as defined in claim 1).
R5 = H, pyridine, imidazole, pyrrole, indole, triazole, pyrrolidine, piperidine;
X=O;
Q=single bond, CO, CONR, NR (wherein R is as defined in claim 1);
W=H, F, Cl, Br, Me, t-butyl, C1-8alkoxy, 2,5-dimethylhexyl, trifluoromethyl, 2,5-(di-trifluoromethyl)-phenyl, 4-methoxy-phenyl, 4-fluoro-phenyl, phenyl, phenyl-C1-8alkyl, C1-8alkylcarbonyl, phenylcarbonyl;
n=1 and 2;
R1, R2, R3, R4, R6 =H, Me, CN, phenyl, COOR, CONRR' (wherein R and R' are as defined in claim 1).
3. Benzo[c]quinolizine compounds according to claims 1 or 2 of formula 1,2,4,4a,5,6 hexahydro-(11H)-benzo[c]quinolizine-3-one;
8-chloro-1,2,4,4a,5,6 hexahydro-(11H)-benzo[c]quinolizine-3-one;
1,2,4,4a,5,6 hexahydro-8-methyl (11H)-benzo[c]quinolizine-3-one;
1,2,4,4a,5,6 hexahydro-1-methyl (11H)-benzo[c]quinolizine-3-one;
1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
8-chloro-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
8-methyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4-methyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
1-methyl-1,2,4,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
5,6-dihydro-(11H)-benzo[c]quinolizine-3-one;
8-chloro-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
8-chloro-1-methyl-4,4a,5,6-tetrahydro-(11H)-benzo[c]quinolizine-3-one;
8-methyl-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4-methyl-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one (cis) and (trans);
8-chloro-4-methyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4,8-dimethyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4,8-dimethyl-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one (cis) and (trans);
8-chloro-4-methyl-4,4a,5,6-tetrahydro-(11H)-benzo[c]quinolizine-3-one (cis) and (trans).
8-chloro-1,2,4,4a,5,6 hexahydro-(11H)-benzo[c]quinolizine-3-one;
1,2,4,4a,5,6 hexahydro-8-methyl (11H)-benzo[c]quinolizine-3-one;
1,2,4,4a,5,6 hexahydro-1-methyl (11H)-benzo[c]quinolizine-3-one;
1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
8-chloro-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
8-methyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4-methyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
1-methyl-1,2,4,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
5,6-dihydro-(11H)-benzo[c]quinolizine-3-one;
8-chloro-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
8-chloro-1-methyl-4,4a,5,6-tetrahydro-(11H)-benzo[c]quinolizine-3-one;
8-methyl-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4-methyl-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one (cis) and (trans);
8-chloro-4-methyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4,8-dimethyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4,8-dimethyl-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one (cis) and (trans);
8-chloro-4-methyl-4,4a,5,6-tetrahydro-(11H)-benzo[c]quinolizine-3-one (cis) and (trans).
4. Process for the preparation of compounds according to any one of claims 1 to 3 wherein:
the amide-group of a compound of formula (2) is protected with a protecting group Z to give the compound (3) the above said compound (3) is reduced to compound (4) and compound (4) is reacted with a silylether (6) prepared "in situ" by resting a vinyl-ketone (5) (wherein R1, R2, R6 are as defined in claim 1) with a silylating agent, and are finally hydrolized to give the final compound of formula (I) wherein X = 0.
the amide-group of a compound of formula (2) is protected with a protecting group Z to give the compound (3) the above said compound (3) is reduced to compound (4) and compound (4) is reacted with a silylether (6) prepared "in situ" by resting a vinyl-ketone (5) (wherein R1, R2, R6 are as defined in claim 1) with a silylating agent, and are finally hydrolized to give the final compound of formula (I) wherein X = 0.
5. Process according to claim 4 wherein a double bond is introduced in position a or b of formula (I) by reaction of dichlorodicyanoquinone (DDQ) with the corresponding silylenolethers or by oxidation with quicksilver (mercury) acetate of the saturated compound obtained according to claim 4 and the possible transformation of the group X is performed via the corresponding enoltriflates and following carbonylation in the presence of palladium diacetate, triphenylphosphine and suitable nucleophilic reagent.
6. Compound of formula (4) wherein W, Q, n, R3, R4, R5 are as defined in claim 1 and Z is a carboxy or thiocarboxy ester protecting group for the amide-group with the proviso that when R3 = R4 = R5 = (WQ)n = H then Z is not a -COO-lower alkyl group or a -CSO-lower alkyl group.
7. Pharmaceutical composition wherein the active principle is a compound of formula (I) wherein:
R1, R2, R3, R4, R6, same or different, are chosen in the group consisting of:
H, C1-8alkyl, C2-8alkenyl, C2-8alkinyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camphane, adamantine, phenyl, naphthyl, pyridine, imidazole, pyrrole, indole, triazole, pyrrolidine, piperidine, halogen, CN, azide, NRR', C1-8alkylamino, phenylamino, naphthylamino, C1-8alkyloxy, phenyloxy, naphthyloxy, COOR, CONRR' wherein R and R', same or different, are chosen in the group consisting of: H, C1-8alkyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camphane, adamantine, phenyl, naphthyl, pyridine, imidazole, pyrrole, indole, triazole, pyrrolidine, piperidine, phenylC1-8alkyl, naphthylC1-8alkyl;
R5 is chosen in the group consisting of: H, C1-8alkyl, COOR, CN, phenyl, naphthyl, pyridine, imidazole, pyrrole, indole, triazole, pyrrolidine, piperidine;
X is chosen in the group consisting of: 0, C(=O)R, COOR, NO2, CONR'R
wherein R and R' are as above defined;
Q is chosen in the group consisting of: single bond, C1-8alkyl, C2-8alkenyl, C2-8alkinyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclo-heptane, cyclooctane, norbornane, camphane, adamantine, CO, CONR, NR, wherein R is as above defined;
W is chosen in the group consisting of: H, C1-8alkyl, C2-8alkenyl, C2-8alkinyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camphane, adamantane, trifluoromethyl, C1-8alkoxy, C1-8alkoxy-C1-8alkyl, phenylC1-8alkyl, naphthylC1-8alkyl, phenyl, naphthyl, phenyloxy, naphthyloxy, phenylamino, naphthylamino, C1-8alkylcarbonyl, phenylcarbonyl, naphthylcarbonyl, halogen, CN, NRR', C1-8alkylamino, pyridine, imidazole, pyrrole, indole, triazole, pyrrolidine, piperidine, wherein the groups alkyl, alkenyl, alkinyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camphane, adamantine, phenyl, naphthyl, pyridine, imidazole, pyrrole, indole, triazole, pyrrolidine, piperidine can be substituted by halogen, OR, phenyl, NRR', CN, COOK, CONRR', C1-8alkyl (wherein R and R' are as above defined);
n is an integer comprised between 1 and 4;
the symbol means that the corresponding bonds a, b, c, d e, f, and g can be single or double bonds; with the proviso that when b or f are a double bond then the group R5 is absent;
their pharmaceutically acceptable salts or esters or mixtures thereof in combination with the suitable pharmaceutical acceptable excipients.
R1, R2, R3, R4, R6, same or different, are chosen in the group consisting of:
H, C1-8alkyl, C2-8alkenyl, C2-8alkinyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camphane, adamantine, phenyl, naphthyl, pyridine, imidazole, pyrrole, indole, triazole, pyrrolidine, piperidine, halogen, CN, azide, NRR', C1-8alkylamino, phenylamino, naphthylamino, C1-8alkyloxy, phenyloxy, naphthyloxy, COOR, CONRR' wherein R and R', same or different, are chosen in the group consisting of: H, C1-8alkyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camphane, adamantine, phenyl, naphthyl, pyridine, imidazole, pyrrole, indole, triazole, pyrrolidine, piperidine, phenylC1-8alkyl, naphthylC1-8alkyl;
R5 is chosen in the group consisting of: H, C1-8alkyl, COOR, CN, phenyl, naphthyl, pyridine, imidazole, pyrrole, indole, triazole, pyrrolidine, piperidine;
X is chosen in the group consisting of: 0, C(=O)R, COOR, NO2, CONR'R
wherein R and R' are as above defined;
Q is chosen in the group consisting of: single bond, C1-8alkyl, C2-8alkenyl, C2-8alkinyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclo-heptane, cyclooctane, norbornane, camphane, adamantine, CO, CONR, NR, wherein R is as above defined;
W is chosen in the group consisting of: H, C1-8alkyl, C2-8alkenyl, C2-8alkinyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camphane, adamantane, trifluoromethyl, C1-8alkoxy, C1-8alkoxy-C1-8alkyl, phenylC1-8alkyl, naphthylC1-8alkyl, phenyl, naphthyl, phenyloxy, naphthyloxy, phenylamino, naphthylamino, C1-8alkylcarbonyl, phenylcarbonyl, naphthylcarbonyl, halogen, CN, NRR', C1-8alkylamino, pyridine, imidazole, pyrrole, indole, triazole, pyrrolidine, piperidine, wherein the groups alkyl, alkenyl, alkinyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camphane, adamantine, phenyl, naphthyl, pyridine, imidazole, pyrrole, indole, triazole, pyrrolidine, piperidine can be substituted by halogen, OR, phenyl, NRR', CN, COOK, CONRR', C1-8alkyl (wherein R and R' are as above defined);
n is an integer comprised between 1 and 4;
the symbol means that the corresponding bonds a, b, c, d e, f, and g can be single or double bonds; with the proviso that when b or f are a double bond then the group R5 is absent;
their pharmaceutically acceptable salts or esters or mixtures thereof in combination with the suitable pharmaceutical acceptable excipients.
8. Pharmaceutical composition according to claim 7 for use in the inhibition of the 5alphaR-I and/or 5alphaR-II iso-enzymes.
9. Pharmaceutical composition according to claims 7 and 8 in the form suitable for topical use.
10. Use of a pharmaceutical composition according to claim 7 for the treatment of acne, baldness, prostatic cancer and prostatic hypertrophy in men and hirsutism in women.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITFI96A000019 | 1996-02-09 | ||
| IT96FI000019A IT1286545B1 (en) | 1996-02-09 | 1996-02-09 | BENZO (C) QUINOLYZINE DERIVATIVES, THEIR PREPARATION AND USE AS 5-ALPHA-REDUCTASE INHIBITORS |
| PCT/EP1997/000552 WO1997029107A1 (en) | 1996-02-09 | 1997-02-07 | BENZO[C]QUINOLIZINE DERIVATIVES, THEIR PREPARATION AND USE AS 5α-REDUCTASES INHIBITORS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2245758A1 CA2245758A1 (en) | 1997-08-14 |
| CA2245758C true CA2245758C (en) | 2006-04-11 |
Family
ID=29421798
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2245758 Expired - Fee Related CA2245758C (en) | 1996-02-09 | 1997-02-07 | Benzo[c]quinolizine derivatives, their preparation and use as 5.alpha.-reductases inhibitors |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2245758C (en) |
-
1997
- 1997-02-07 CA CA 2245758 patent/CA2245758C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CA2245758A1 (en) | 1997-08-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2027245C (en) | Process for 1h-imidazo[4,5-c]quinolines | |
| AU711886C (en) | Benzo(C)quinolizine derivatives, their preparation and use as 5alpha-reductases inhibitors | |
| EP1102765B1 (en) | PROCESS FOR THE SYNTHESIS OF (1$i(H))-BENZO C]QUINOLIZIN-3-ONES DERIVATIVES | |
| CA2245758C (en) | Benzo[c]quinolizine derivatives, their preparation and use as 5.alpha.-reductases inhibitors | |
| EP1066284B1 (en) | Benzo(c)quinolizine derivatives and their use as 5 alpha-reductases inhibitors | |
| AU5128599A (en) | Tricyclic compounds | |
| KR100330141B1 (en) | Preparation of 6-fluoro-2-halogenquinoline | |
| JPH0616628A (en) | Indole derivative | |
| JPH03275672A (en) | Cyclopenta(b)quinoline derivative | |
| JPH0570458A (en) | Pyrroloquinoline quinone derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |