CA2135926C - Substituted hexahydrobenzo[a]phenanthridines - Google Patents

Abstract

Trans-hexahydrobenzo[a]phenanthridine of formula (I) wherein R is hydrogen or C1-C4 alkyl; R1 is hydrogen or a phenoxy protecting group, X is fluoro, chloro, bromo, iodo or a group of the formula -OR5, and R2, R3, and R4 are independently selected from the group consisting of hydrogen, C1-C4 alkyl, phenyl, fluoro, chloro, bromo, iodo, or a group -OR1 provided that at least one of R2, R3, and R4 are other than hydrogen, are novel ligands for dopamine receptors.

Description

WHO 93/24462 ~; ~ ~ ' ~ ~ ~ PCT/US93/(~4971 _1_ SUBSTITUTED-HEXAHYDR~BENZ~[AJPI-IENANTHRlDINES
Field of Pnvention This invention relates to novel ligands for dopamine receptors.
More particularly, this invention is directed to certain substituted trans-hexahydrobenzo[a]phenanthridine compounds useful as dopamine-like agents or dopamine receptor blockers.
Background and Summar~of the Invention Dopamine, a neurotransmitter in the central nervous system ('°CNS"), has been implicated in numerous neurological disorders. For example; it has been hypothesized that excess stimulation of dopamine receptor subtypes may be linked to schi~aphrenia. Additiona!!y, it !s generally recognized that either excessive or insufficient functional dopaminergic activity in the centre! nervous system may cause hypertension, narcolepsy, and other behavioral, neurological, physiological, and movement disorders including Parkinson's disease, a chronic, progressive disease characterized by an inability to control the voluntary motor system.
It is generally accepted that there are at least two pharmacological subtypes of dopamine receptors (D-1 and D-2), each consisting of several molecular forms. While the physiological activities associated with the interaction with dopamine with those respective receptor subtypes are not fully understood, it is known that ligands exhibiting selectivity for, activation/blockade with one or the other of the receptor subtypes produce more or less predictable, neuropharmacoiogical results. CNS drugs exhibiting affinity for the dopamine receptors are generally classified not only by their receptor selectivity, but further by the character of their receptor interaction, i.e., by their agonist (receptor stimulating] or antagonist (receptor blocking) activity. More recently, it has ..:. ... , ~ ~;,.~_..

2 ~ ~ ~ ~ a PCT/U~93/0~~~1 been suggested that dopamine receptor ligands may further be characterized by selectivity for either presynaptic or postsynaptic receptors. As the neuropharmacoiogical effects caused by assaciation of selective ligands , (agonist vs. antagonist) with specific receptor subtypes becomes better understood, drug researchers will be much better positioned to design CNS
drugs targeting specific neurological or psychiatric disorders. Drugs with the ability to selectively block or stimulate D-1 or D-2 dopamine receptors are flf significant interest in the CNS medical research community.
The present invention provides novel CZ, C3, and/or C4-substituted traps-5,6,6a,7,8,12b-hexahydrobenzo[a~phenanthridines. They are related generally to the compounds described in co-owned U.S. Patent No. 5,047,536, issued September 10, 1991, including particularly the compound traps-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]
phenanthridine (dihydrexidinel, a D-1 agonist which has been the subject of much study over the past several years. The biological activities of the present compounds vary significantly in their selectivity for the dopamine receptor subtypes, depending on the nature and positioning of the substituent groups. Substitution at the C2, C3, and/or C4 position on the benzopheryanthridine ring system has been found to provide a means for controlling receptor affinity and concomitantly receptor selectivity. Thus, for example, 2-methyidihydrexidine has D-1 potency and efficacy comparable to dihydrexidine, while it has a five fold enhanced selectivity for the D-1 receptor. In contrast, the compound 3-methyidihydrexidine while retaining potency and efficacy as dihydrexidine, has greater D-2 potency, . 25 making it less selective but able to activate better both types of receptors'.
Further, data on the present substituted hexahydrobenzo[a] phenanthridines suggest that the D-2 affinity is selective for postsynaptic dopamine D-2 receptors: It is anticipated that the present ligands will offer significant therapeutic benefit over compounds exhibiting presynaptic D-2 effects because they should evoke less neural accommodation of the dopamine ,~~.3~9~~i neurons. The postsynaptic D-2 selectivity of dihydrexidine itself and the present 2-, 3-, andlor 4-substituted dihydrexidine compounds is without antecedent in the art.
The present compounds can be administered by oral or parenteral routes of administration in amounts effective to evoke therapeutic responses in patients suffering from, for example, hypertension, Parkinson's disease, attention deficit disorder, narcolepsy, schizophrenia, other psychiatric conditions, and other diseases deriving from central nervous system dysfunction.
Additional objects, and advantages of the invention will become apparent to those skilled in the art upon consideration of the following detailed description of preferred embodiments exemplifying the best mode of carrying out the invention.
Detailg~,~~scrirtion of the Invention There is provided by this invention substituted hexahydrobenxo[a)phenanthridine compounds of the general formula .~j R2w ~4~R4 i' s Ha Ri O ii 12 ~ N-R
c l0 ~ Hb , X ~ 7 and pharmaceutically acceptable salts thereof, wherein H, and H~ are traps across ring fusion bond c; R is hydrogen or C1 - C4 alkyl; R~ is ' . , ,, WO 93/24462 :a ~~ ~.~ a.~. :~ ~ ~. PCT/US931U4971 hydrogen or a phenoxy protecting group; X is fluoro, chloro, bromo, or iodo, or a group of the formula -OR5 wherein R5 is hydrogen or a phenoxy protecting group, provided that when X is a group of the formula -ORS, the groups R, and R5 can be taken together to form a -CH2- group, thus representing a methylenedioxy functional group bridging the C-10 and C-11 positions on the hexahyrobenzo(a)phenanthridine ring system f as labelled above in Formula ID: and R2, R3v and R4 are independently selscted from the group consisting of hydrogen, C~ - C4 alkyl, phenyl, fluoro, chloro, bromo, iodo, or a group -ORS wherein R~ is as defined above, provided that at least one of R2, R3, and R4 are other than hydrogen.
The term "C, - Cd alkyl" as used herein refers to branched or straight chain alkyl groups comprising one to four carbon atoms, including, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butt'! and cyclopropylmethyl.
The term "pharmaceutically acceptable salts" refers to those salts which are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable salts are well known in the art. The salts can be prepared according to conventional methods in situ during the final isolation and purification of the compounds, or separately by reacting the free base with a suitable organic acid.
The term "phenoxy protecting group" as used herein refers to substituents on the phenolic oxygen which prevent undesired reactions and degradations during synthesis and which can be removed later without effect on other functional groups on the molecule. Such protecting groups , and the methods for their application and removal are well known in the art.
They include ethers, such as methyl, isopropyl, t-butyl, cyclopropylmethyl, ' cyclohexyl, allyl ethers and the like; alkoxyalkyi ethers such as methoxymethyl or methoxyethoxymethyl ethers and the like: alkylthioaikyl ethers such a methylthiomethyl ethers; tetrahydropyranyl ethers; arylalkyl ethers such as benzyl, o-nitrobenzyl, p-methoxybenzyl, 9-anthrylmethyl, 4-picolyl ethers and the like; trialkylsilyl ethers such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl ethers and the like; alkyl and aryl esters such as acetates, propionates, n-butyrates, isobutyrates, trimethylacetates, benzoates and the like; carbonates such as methyl, ethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, vinyl, benzyl and the like; and carbamates such as methyl, isobutyl, phenyl, benzyl, dimethyl and the like.
The term "C1 - C9 alkoxy" as used herein refers to branched or straight chain alkyl groups comprising one to four carbon atoms bonded through an oxygen atom, including, but not limited to, methoxy, ethoxy and t-butoxy.
The compounds of this invention are prepared using the same preparative chemical steps described for the preparation of the hexahydrobenzo[a]phenanthridine compounds described and claimed in U.S. Patent No. 5,047,536, issued September 10, 1991. The present compounds are prepared using the chemical reactions depicted in the reaction scheme illustrated in Figs. 1 and 2 of U.S. Patent No. 5,047,536 using the appropriately substituted benzoic acid acylating agent starting material instead of the benzoyl chloride reagent used in the initial reaction step. Thus, for example, use of 4-methylbenzoyl chloride will yield a 2-methyl hexahydrobenzo[a]phenanthridine compound of the present invention.
According to one aspect of the present invention, there is provided a compound of the formula -5a-R2 \ Ra Hai.,, I
RIO. / ~ ~ N~R
~Hb X
or a pharmaceutically acceptable salt thereof wherein Ha and Hb are trans across ring fusion bond c, R is hydrogen or C1-C4 alkyl; R1 is hydrogen or a phenoxy protecting group;
X is a group of the formula -OR5 wherein R5 is hydrogen or a phenoxy protecting group, and providing that the groups R1 and R5 can be taken together to form a group of the formula -CH2-; and R2, R3 and R4 are independently selected from the group consisting of hydrogen, C1-C9 alkyl, phenyl, fluoro, chloro, bromo, iodo, and a group -OR1 wherein R1 is as defined above, provided that at least one of R2, R3 and RQ
is other than hydrogen.
According to another aspect of the present invention, there is provided a use of a compound or salt described herein, for treating a dopamine-related dysfunction of the central nervous system evidenced by an apparent neurological, psychological, physiological, or behavioral disorder.
According to still another aspect of the present invention, there is provided a pharmaceutical composition for treating dopamine-related dysfunction of the central nervous system evidenced by an apparent neurological, physiological, psychological, or behavioral disorder, said composition comprising a therapeutically effective amount -5b-of the compound or salt described herein and a pharmaceutically acceptable carrier therefor.
According to yet another aspect of the present invention, there is provided a use of a compound exhibiting selective postsynaptic dopamine D-2 receptor affinity for treating a dopamine-related dysfunction of the central nervous system characterized by an apparent neurological, physiological, psychological, or behavioral disorder, where the compound is of the formula R2 \ R4 Ha i.,. I
R,o r ~ . c NCR
Hb or a pharmaceutically acceptable salt thereof, wherein the Ha and Hb are trans across ring fusion bond c; R is hydrogen or C1-CQ alkyl; R1 is hydrogen or a phenoxy protecting group; X is a group of the formula -OR5 wherein RS is hydrogen or a phenoxy protecting group, and providing that the groups R1 and RS can be taken together to form a group of the formula -CHZ-; and R2, R3 and R4 are independently selected from the group consisting of hydrogen, C1-C4 alkyl, phenyl, fluoro, chloro, bromo, iodo, and a group -OR1 wherein R1 is as defined above.
~wamT n 2-(N-benzyl-N-4-methylbenzoyl)-6,7-dimethoxy-3,4-dihydro-2-naphthylamine. To a solution of 4.015 g (19.5 mmol) of 6,7-dimethoxy-(3-tetralone in 100 ml of toluene was added 2.135 g (1.025 equiv.) of benzylamine.
The reaction was heated at reflux overnight under N2 with -5c-continuous water removal. The reaction was cooled and the solvent was WO 93/24462 PC,'T/U~93/Oa~7I

removed by rotary vacuum evaporation to yield the crude N-benzyl enamine as a brown oil.
Meanwhile, the 4-methylbenzoyl chloride acylating agent was prepared by suspending 3.314 g (24.3 mmol) of p-toluic acid in 200 ml benzene. To this solution was added 2.0 equiv. (4.25 ml) of oxalyl chloride, dropwise via a pressure-equalizing dropping funnel at 0°C. DMF (2-3 drops) was added to the reaction mixture cataiytically and the ice bath was removed. The progress of the reaction was monitored via infrared spectroscopy. The solvent was removed by rotary vacuum evaporation and the residual oil was pumped down under high vacuum overnight.
The crude N-benzyl enamine residue was dissolved in 100 ml of CH2CiZ, and to this solution was added 2.02 g (19.96 mmoi) of triethylamine at 0°C. 4-methylbenzoyl chloride (3.087 g, 19.96 mmol) was dissolved in 20 ml CH2C12 and this solution was added dropwise to the cold, stirring N-benzyl enamine solution. The reaction was allowed to warm to room temperature and was left to stir under N2 overnight. The reaction mixture was washed successively with 2 x 30 ml of 5 % aqueous HCI, 2 x 30 ml of saturated sodium bicarbonate solution, saturated NaCI solution, and was dried over MgS04. After filtration, the filtrate was concentrated under vacuum. Crystallization from diethyl ether gave 5.575 g (69.3%) of the enamide mp 96-98°C. CIMS (isobutane); M + 1 414; 'H-NMR (CDC13);
d' 7.59 (d, 2, ArH), 7:46 (m, 3, ArH), 7.35 (m, 3, ArH), 7.20 (d, 2, ArH), 6.60 (s, 1, ArH), 6.45 (s, 1, ArH), 6.18 (s, 1, ArCH), 5.01 (s, 2, ArCH2N), 3.80 (s, 3, OCH3), 3.78 (s, 3, OCH3), 2.53 (t, 2, ArCH2), 2.37 (s, 3, ArCH3), 2.16 (t, 2, CH2); Anal. (C2~H2sN03) C, H, N, Traps-2-methyl-6-benzyl-10,11-dimethoxy-5,6,6a,7,8,12b- .
hexahydro-benzo[a]phenanthridine-5-one. A solution of 4.80 g (11.62 mmol) of the 6,7-dimethoxy enamide prepared above, in 500 mi of THF, was introduced to an Ace Glass 500 ml photochemical reactor. This solution was stirred while irradiating for 2 hours with a 450 watt Hanovia W~ 93/24462 , r .~, ~ j J ~ ~ ~ PCT/US93/04971 -7_ medium pressure, quartz, mercury-vapor lamp seated in a water cooled, quartz immersion well. The solution was concentrated in vacuo and crystallized from diethyl ether to provide 2.433 (50.7%) of the 10, 1 1-dimethoxy lactam, mp 183-195°C. C1MS (isobutane); M + 1 414; 'H-NMI~
(CDCi3); d 8.13 (d, 1, ArH), 7.30 (s, 1, ArH), 7.23 (m, 6, ArH), 6.93 (s, 1, ArH), 6.63 (s, 1, ArH), 5.38 (d, 1, ArCHaN), 5.30 (d, 1, ArCHaN), 4.34 (d, 1, AraCH, J =11.4 Hz), 3.89 (s, 3, OCH3), 3.88 (s, 3, OCH3), 3.76 (m, 1, CHN), 2.68 (m, 2, ArCHa), 2.37 (s, 3, ArCH3), 2.25 (m, 1, CH2CN), 1.75 (m, 1, CH2CN); Anal. (Ca7H2~N0a) G, H, N.
Trans-2-methyl-6-benzyl-10,11-dimethoxy-5,6,6a,7,8.12b-hexahydrobenzo[a)phenanthridine hydrochloride. A solution of 1.349 g 43.27 mmol) of the iactam prepared above, in 100 m1 dry THF was cooled in an ice-salt bath and 4.0 equiv. (13.0 ml) of i .0 molar BH3 was added via syringe. The reaction was heated as reflux under nitrogen overnight.
Methanol (10 mi) was added dropwise to the reaction mixture and reflux was continued for 1 hour. The solvent was removed by rotary vacuum evaporation. The residue was chased two times with methanol and twice with ethanol. The flask was placed under high vacuum (0.05 mm Hg) overnight. The residue was dissolved in ethanol and was carefully acidified with concentrated HCI. The vioiatiles were removed and the product was crystallized from ethanol to afford 1.123 g (78.9%) of the hydrochloride salt, mp 220-223°C. CIMS (isobutane); M + 1 400; 'H-NMF~ (CDC13, free base); d 7.37 (d, 2, ArH), 7.33 (m, 2, ArH), 7.26 (m, 1, ArH), 7.22 (s, 1, ArH), 7.02 (d, 1, ArH), 6.98 (d, 1, ArH), 6.89 fs, 1, ArH), 6.72 (s, 1, ArH), 4.02 (d, 1, AraCH, J =10.81 Hz), 3.88 (s, 3, OCH3), 3.86 (d, 1, ArCHZN), 3.82 (m, 1, ArCHaN), 3.78 (s, 3, OCH3), 3.50 (d, 1, ArCH2N), 3.30 (d, 1, ArCH2N), 2.87 (m, 1, ArCHa), 2.82 (m, 1, CHN), 2.34 (m,1, CHaCN), 2.32 (s. 3, ArCH3), 2.20 (m, 1, ArCHa), 1.93 (m, 1, CH2CN); Anal. (Ca,Ha9N0a) C, H, N.

_g_ Traps-2-methyl-10.11-dimethoxy-5,6,6a,7.8.12b-hexahydro-benzofa)phenanthridine hydrochloride. A solution of 0.760 .g (1.75 mmol) of the 6-benzyl hydrochloride salt prepared above in 100 ml of 95% ethanol containing 150 mg of 1086 Pd/C catalyst was shaken at room temperature under 50 psig of H2 for 8 hours. After removal of the catalyst by filtration through Celit~, the solution was concentrated to dryness under vacuum and the residue was recrystallized from acetonitrile to afford 0.520 g 186.2%) of the crystalline salt, mp 238-239°C. CIMS (isobutane); M + 1 310; 'H-NMR (DMSO, HCI SAIT); d 10.04 (s. 1, NH), 7.29 ~d, 1, ArH), 7.16-(m, 2, ArH). 6.88 (s. 1. ArH). 6.84 (s, 1, ArH), 4.31 (s. 2, ArCHZN), 4.23 Id. 1, Ar2CH. J =10.8 Hz), 3.76 (s, 3, OCH3), 3.70 (s, 3, OCH3), 2.91 (m, 2, ArCH?), 2.80 (m. 1, CHN). 2.49 (s. 3, ArCH3), 2.30 (m, 1, CH2CN), 2.09-(m, 1, CHzCN); Anal. (C2°Hz3NO=) C. H, N.
Traps-2-methyl-10,11-dihydroxy-5,6.6a,7,8,12b-hexahydro-benzofalphenanthridine hydrochloride. 0.394 g (1.140 mmol) of the 0.0-dimethyl hydrochloride salt prepared above was converted to its free base.
The free base was dissolved in 35 ml of dichloromethane and the solution was cooled to -78°C. 4.0 equiv. (4.56 ml) of a 1.0 molar solution of 8Br3 was added slowly via syringe. The reaction was stirred under N2 overnight with concomitant warming to room temperature. 7.0 ml of methanol was added to the reaction mixture and the solvent was removed by rotary vacuum evaporation. The flask was placed under high vacuum (0.05 mm Hg) overnight. The residue was dissolved in water and was carefully neutralized to its free base initially with sodium bicarbonate and finally with ammonium hydroxide (1-2 drops). The free base was isolated by suction filtration and was washed with cold water. The filtrate was extracted several times with dichloromethane and the organic extacts were dried, filtered and concentrated. The filter cake and the organic residue were combined, dissolved in ethanol and carefully acidified with concentrated HCI. After removal of the volatiles, the HCI salt was crystallized as a ' .. ' . ' , ,.. , .. . . ... . ~ ... , ~... .,. , . ~'~. . ~, ~.. .. 1....
'., ...,.. ., ... ~,.v - .'..' '. . . ~~ .. ~ , . ',.,'. . ~. .. '.. '~' .., ..-..~, " .' ,, .,~,, ., ., ., . ,,~ .p ~ .., :;., , .~.: ..' W~O 93/24462 ' ~ -~ ~ r~ ~r ~ a YCTI U593/U4971 _g_ solvate from methanol in a yield of 0.185 g (51 %), mp (decomposes [~
190°C). C1MS fisobutane); M + 1 282; 'H-NMR (DMSO, HCi salt); cS 9.52 (s, 1, NH), 8.87 (d, 2, OH), 7.27 (d, 1, ArH), 7.20 (s, 1, ArH), 7.15 (d, 1, ArH), 6.72 (s, 1, ArH), 6.60 (s, 1, ArH), 4.32 (s, 2, ArCH2N), 4.10 (d, 1, ArCHaCH, J =1 1.26 Hz), 2.90 (m, 1, CHN), 2.70 (m, 2, ArCH2), 2.32 (s, 3, ArCH3), 2.13 (m, 1, CH2CN), 1.88 (m, 1, CHZCN); Anal. (C,8H~9N0z) C, H, N.

2-~N-benzyl-N-3-methylbenzoyl)-6,7-dimethoxy-3,4-dihydro-2-naphthylamine. To a solution of 3.504 g (17.0 mmol) of 6,7-dimethoxy-~B-tetralone in 100 ml of toluene was added 1.870 g (1.025 equiv.) of benzylamine. The reaction was heated at refiux overnight under N~ with continuous water removal. The reaction was cooled and the solvent was removed by rotary vacuum evaporation to yield the crude N-benzyl enamine as a brown oil.
Meanwhile, t~~e 3-methylbenzoyf chloride acylating agent was prepared by suspending 3.016 g (22.0 mmol) of m-toluic acid in 100 mi benzene. To this solution was added 2.0 equiv. (3.84 ml) of oxalyl chloride, dropwise via a pressure-equalizing dropping funnel at 0°C. DMF (2-3 drops) was added to the reaction mixture catalytically and the ice bath was removed. The progress of the reaction was monitored via infrared spectroscopy. The solvent was removed by rotary vacuum evaporation and the residual oil was pumped down under high vacuum overnight.
The crude N-benzyl enamine residue was dissolved in 100 ml of CM2CI2, and to this solution was added 1.763 g ( 17.42 mmol) of triethylamine at 0°C. 3-methylbenzoyl chloride (2.759 g, 17.84 mmol) was dissolved in 20 ml CH2CI2 and this solution was added dropwise to the cold, stirring N-benzyl enamine solution. The reaction was allowed to warm to room temperature and was left to stir under N2 overnight. The reaction mixture was washed successively with 2 x 30 ml of 5% aqueous HC1, 2 x WO 93124402 PC'T/U593/Oa,971 30 ml of saturated sodium bicarbonate solution, saturated NaCI solution, and was dried over MgSO4. After filtration, the filtrate was concentrated under vacuum. Crystallization from diethyl ether gave 4.431 g (63.1 %) of , the enamide mp 96-97°C. C1MS (isobutanel; M + 1 414; 'H-NMR (0D013);
S 7.36 (s, 1, ArH), 7.26 (m, 3, ArH), 7.20 (m, 5, ArH), 6.50 (s, 1, ArH), 6.40 (s, 1, ArHD, 6.05 (s, 1, ArCHD, 4.95 (s, 2, ArCHaN), 3.75 (s, 3, OCH3), 3.74 (s, 3; OCH3), 2.43 (t, 2, ArCHa), 2.28 (s, 3, ArCH3), 2.07 (t, 2, CH2);
Anal. (Ca~Hz~N03) C; H, N.
Traps-3-methyl-6-benzyl-10,11-dimethoxy-5,6, 6a,7,8,12b-hexahydrobenzo[a~phenanthridine-5-one. A solution of 1.922 g (4.65 mmol) of the 6,7-dimethoxy enamide prepared above, in 500 m9 of THF, was introduced to an Ace Glass 500 ml photochemical reactor. This solution was stirred while irradiating for 5 hours with a 450 watt Hanovia medium pressure, quartz, mercury-vapor lamp seated in a water cooled, quartz immersion welt. The solution was concentrated in vacuo and crystallized from diethyl ether to provide 0.835 g (43.4%) of the 10, 11-dimethoxy lactam, mp 154-157°C. CIMS (isobutane); M + 1 414; 'H-NMR
(0D013); d 7.94 (s, 1, ArH), 7.34 (d, 1, ArH), 7.17 (m, 6, ArH), 6.84 (s, 1, ArH), 6.54 (s, 1, ArH), 5.28 (d, 1, ArCHZN), 4.66 (d, 1, ArCH2N), 4.23 Id, 1, AraCH, J =11.4 Hz), 3.78 (s, 3, OCH3), 3.74 (s, 3, OCH3), 3.61 (m, 1, CHN), 2.59 (m, 2, ArCHaI, 2.34 (s, 3, ArCH3), 2.15 (m, 1, CH2CN), 1.63 (m, 1, CHaCN); Anal. (Ca~Ha~N03) C, H, N.
t ' Traps-3-m~ti-dyl-6-benzyl-10,11-dimethoxy-5,6,,6a,7,8,12b-hexahydrobenzo[a]phenanthridine hydrochloride. A solution of 0.773 g ( 1.872 mmol) of the lactam prepared above, in 50 ml dry THF was cooled in an ice-salt bath and 4.0 equiv. (7.5 ml) of 1.0 molar BHa was added via syringe. The reaction was heated as reflux under nitrogen overnight.
Methanol t6 ml) was added dropwise to the reaction mixture and reflux was continued for 1 hour. The solvent was removed by rotary vacuum evaporation. The residue was chased two times with methanol and twice with ethanol. The flask was placed under high vacuum (0.05 mm Hg) overnight. The residue was dissolved in ethanol and was carefully acidified with concentrated HCI. The violatiles were removed and the product was crystallized from ethanol to afford 0.652 g (80°r6) of the hydrochloride salt, mp 193-195°C. CIMS (isobutane); M + 1 400; 'H-NMR (CDCI3, free Basel;
d 7.38 (d, 2, ArH), 7.33 (m, 2, ArH), 7.28 (m, 2, ArH), 7.07 (d, 1, ArH), 6.90 (s, 1, ArH), 6.88 (s, 1, ArHI, 6.72 (s, 1, ArH), 4.02 (d, 1, ArZCH, J =11.2 Hz), 3.90 (d, 1, ArCH2N), 3.87 (s, 3, OCH3), 3.82 (m, 1, ArCH2N), 3.78 (s, 3, OCH3), 3.48 Id, 1, ArCH2N), 3.30 (d, 1, ArCH2N), 2.88 (m, 1, ArCH2), 2.82 lm, 1, CHN), 2.36 (m, 1, CH2CN), 2.32 (s, 3, ArCH3), 2.20 (m, 1, ArCHT), 1.95 (m, 1, CH2CN1; Anal. IC2~H2gNO2) C, H, N.
Traps-3-methyl-10,11-dimethoxy-5,6,6a,7,8,12b-hexahydro-benzo[a]phenanthridine hydrochloride. A solution of 0.643 g 11.47 mmol) of the 6-benzyl hydrochloride salt prepared above in 100 ml of 95°~
ethanol containing 130 mg of 10°~ Pd/C catalyst was shaken at room temperature under 50 psig of H= for 8 hours. After removal of the catalyst by filtration TM
through Celite, the solution was concentrated to dryness under vacuum and the residue was recrystallized from acetonitrile to afford 0.397 g (78%) of the crystalline salt, mp 254-256°C. CIMS (isobutane); M + 1 310; 'H-NMR (DMSO, HCI SALT); a 10.01 (s, 1, NH), 7.36 (d, 1, ArH), 7.09 (d, 1, ArH), 6.98 Is, 1, ArH), 6.92 (s, 1, ArHI, 6.74 (s, 1, ArH), 4.04 (s, 2, ArCH=N1, 3.88 (s, 3, OCH3), 3.81 (s, 3, OCH3), 3.76 Id, 1, Ar2CH), 2.89 (m, 2, ArCH2), 2.70 (m, 1, CHN), 2.36 Is, 3, ArCH3), 2.16 (m, 1, CH2CN), 1.70 Im, 1, CH2CN); Anal. (C~Hz3N02) C, H, N.
Traps-3-methyl-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydro-benzo[a]phenanthridine hydrochloride. 0.520 g (1.51 mmol) of the 0,0-dimethyl hydrochloride salt prepared above was converted to its free base.
The free base was dissolved in 35 ml of dichloromethane and the solution was cooled to -78°C. 4.0 equiv. (6.52 ml) of a 1.0 molar solution of BBr3 was added slowly via syringe. The reaction was stirred under NZ overnight :~I ~ ~ '' ~ ~ ~ PCT/US93/17~971 WO 93/24462 ;. c N ;' _ 12_ with concomitant warming to room temperature. 7.0 ml of methanol was F
added to the reaction mixture and the solvent was removed by rotary ' vacuum evaporation. The flask was placed under high vacuum (0.05 mm Hg) overnight. The residue was dissolved in water and was carefully neutralized to its free base initially with sodium bicarbonate and finally with ammonium hydroxide (1-2 drops). The free base was isolated by suction filtration and was washed with cold water. The filtrate was extracted i several times with dichloromethane and the organic extacts were dried, filtered and concentrated. The filter cake and the organic residue were combined, dissolved in ethanol and carefully acidified with concentrated HCI. After removal of the volatiles, the HCI salt was crystallized as a solvate from methanol in a yield of 0.341 g (71.3%), mp (decomposes C~
190°C). CIMS (isobutane); M + 1 282; 'H-NMR (DMSO, HCi salt); ~ 9.55 (s, 1, NH), 8.85 (d, 2, 0H), 7.30 (d, 1, ArH), 7.22 (s, 1, ArH), 7.20 (d, 1, ArH), 6, fib (s, 1, ArH), 6.60 (s, 1, ArH), 4.31 (s, 2, ArCHZN), 4.09 (d, 1, ArCHZCH, J =11.2 Hz), 2.91 (m, 1, CHN), 2.72 (m, 2, ArCH2), 2.35 (s, 3, ArCH3), 2.16 (rn, 1, CH2CN, 1.85 (m, 1, CH2CN); Anal. (C,eH,9N0z) C, H, N.

2-(N-benzyl-N-3-methylbenzoyl)-6,7-dimethoxy-3,4-dihydro-2-naphthylamine. To a solution of 5.123 g (24.8 mmol) of 6,7-dimethoxy-~-tetralone in 200 ml of toluene was added 2.929 g t 1.025 equiv.) of benzylamine. The reaction was heated at reflux overnight under N2 with continuous water removal. The reaction was cooled and the solvent was removed by rotary vacuum evaporation to yield the crude N-benzyl enamine as a brown oil.
Meanwhile, the 2-methylbenzoyl chloride acylating agent was prepared by suspending 4.750 g (42.2 mmol) of o-toluic acid in 100 ml benzene. To this solution was added 2.0 equiv. (7.37 ml) of oxalyl chloride, dropwise via a pressure-equalizing dropping funnel at 0°C. DMF (2-3 drops) WO 93/24462 ~ ~ ~ ~ ~ ~ PCT/US93104971 _13_ was added to the reaction mixture catalytically and the ice bath was removed. The progress of the reaction was monitored via infrared spectroscopy. The solvent was removed by rotary vacuum evaporation and the residual oil was pumped down under high vacuum overnight.
The crude N-benzyf enamine residue was dissolved in 100 ml of CH~C12, and to this solution was added 2.765 g ( 1.1 equiv. ) of triethylamine at 0°C. 4-methylbenzoyl chloride (4.226 g, 27.3 mmol) was dissolved in 25 ml CH2C12 and this solution was added dropwise to the cold, stirring N-benzyl enamine solution. The reaction was allowed to warm to room temperature and was left to stir under N2 overnight. The reaction mixture was washed successively with 2 x 30 m! of 5% aqueous HCI, 2 x 30 ml of saturated sodium bicarbonate solution, saturated NaCI solution, and was dried ~ver MgSO~. After filtration, the filtrate was concentrated under vacuum. The resulting oil was purified via the chromatotron utilizing a 5 ether/dichloromethane eluent mobile phase to yield 3.950 g (38.5%) of the pure oil. CIMB (isobutane); M + 1 414; 'H-NMR (CDC13); d' 7.34 (d, 2, ArH), 7.30 (m, 2, ArH), 7.25 (d, 2, ArH), 7.14 (m, 2, ArH), 7.07 (m, 1, ArH), 6.47 (s, 1, ArH), 6.37 (s, 1, ArH), 6.04 (s, 1, ArCH), 4.96 (s, 2, ArCH2N), 3.78 (s, 3, OCH3), 3.77 (s, 3, OCH3), 2.39 (s, 3, ArCH3), 2.30 (t, 2, ArCH2), 1.94 (t, 2, CH2).
Trans-4-methyl-~6-benzyl-10,11-dimethoxy-5,6,6a,7,8,12b-hexahydrobenzo[a)phenanthridine-5-one. A solution of 2.641 g (6.395 mmol) of the 6,7-dimethoxy enamide prepared above, in 450 ml of THF, was introduced to an Ace Glass 500 ml photochemical reactor. This solution was stirred while irradiating for 3 hours with a 450 watt Hanovia medium pressure, quartz, mercury-vapor lamp seated in a water cooled, quartz immersion well. The solution was concentrated in vacuo and crystallized from diethyl ether to provide 0.368 (20%) of the 10,11-dimethoxy lactam, mp 175-176°C. CIMS (isobutane); M + 1 414; 'H-NMR
(CDC13); d 7.88 (m, 3, ArH), 7.65 (d, 1, ArH), 7.40 (m, 2, ArH), 7.21 (m, 2, ArH), 6.87 (s, 1, ArH), 6.60 (s, 1, ArH), 5.34 (d, 1, ArCHZN), 4.72 (d, 1, ArCH2N), 4.24 (d, 1, Ar2CH, J =10.9 Hz), 3.86 (s, 3, OCH3), 3.85 (s, 3, OCH3), 3.68 (m, 1, CHN), 2.73 (s, 3, ArCH3), 2.64 (m, 2, ArCH2); 2.20 (m, 1, CH2CN), 1.72 (m, 1, CH2CN).
Trans-4-methyl-6-benzyl-10,11-dimethoxy-5,6,6a.7,8,12b-hexahydrobenzo[a]phenanthridine hydrochloride. A solution of 1.640 g (3.97 mmol) of the lactam prepared above, in 100 ml dry THF was cooled in an ice-salt bath and 4.0 equiv. ( 15.9 ml) of 1.0 molar BH3 was added via syringe. The reaction was heated as reflux under nitrogen overnight.
Methanol (10 ml) was added dropwise to the reaction mixture and reflux was continued for 1 hour. The solvent was removed by rotary vacuum evaporation. The residue was chased two times with methanol and twice with ethanol. The flask was placed under high vacuum (0.05 mm Hg) overnight. The residue was dissolved in ethanol and was carefully acidified with concentrated HCI. The violatiles were removed and the product was crystallized from ethanol to afford 1.288 g (74.5°~6) of the hydrochloride salt, mp 232-235°C. CIMS (isobutane); M + 1 400; 'H-NMR ICDCI3, free base); a 7.38 Id, 2, ArH), 7.33 (m, 2, ArHI, 7.27 (d, 1, ArH), 7.24 (m, 1, ArH), 7.16 (m, 1, ArH), 7.06 (d, 1, ArH), 6.85 (s, 1, ArH), 6.71 (s, 1, ArH), 4.05 (d, 1, Ar~CH, J =10.8 Hz), 3.89 (d, 1, ArCH=N), 3.87 Is, 3, OCH3), 3.82 (m, 1, ArCHzN), 3.76 (s, 3, OCH3), 3.55 (d, 1, ArCH2N), 3.31 (d, 1, ArCH2N), 2.88 Im, 1, ArCH2l, 2.81 (m, 1, CHN), 2.34 Im, 1, CHZCN), 2.20 (m, 1, ArCH2), 2.17 (s, 3, ArCH3), 1.94 Im, 1, CHZCN1.
Trans-4-methyl-10,11-dimethoxy-5,6,6a.7,8,12b-hexahydro-benzota]phenanthridine hydrochloride. A solution of 0.401 g (0.92 mmol) of the 6-benzyl hydrochloride salt prepared above in 100 ml of 95% ethanol containing 100 mg of 10% Pd/C catalyst was shaken at room temperature under 50 psig of Hz for 8 hours. After removal of the catalyst by filtration TM
through Celite, the solution was concentrated to dryness under vacuum and the residue was recrystallized from acetonitrile to afford 0.287 g (90.2%) of WO 93/24462 ' PC'TlIJS93l04971 .~~~.~~926 the crystalline salt, mp 215-216°C. CIMS (isobutane); M + 1 310; 'H-NMR (CDC13, free base); 8 9.75 (s, 1, NH), 7.29 (d, 1, ArH), 7.28 (d, 1, ArH), 7.21 (m, 1, ArH), 6.86 (s, 1, ArH), 6.81 (s, 1, ArH), 4.35 (d, 1, ArCH2N), 4.26 (d, 1, ArCH2N), 4.23 (d, 1, Ar2CH, J =11.17 Hz), 3.75 (s, 3, OCH3), 3.65 (s, 3, OCH3), 2.96 (m, 1, CHN), 2.83 (m, 2, ArCH2), 2.30 (s, 3, ArCH3), 2.21 (m, 1, CH2CN), 1.93 (m, 1, CHZCN).
Trans-4-methyl-10,1 '1-dihydroxy-5,6,6a,7,8,12b-hexahydro-benzo(a3phenanthridine hydrochloride. 0.485 g (1.40 mmoi) of the 0,0-dimethyl hydrochloride salt prepared above was converted to its free base.
The free base was dissolved in 35 ml of dichloromethane and the solution was cooled to -78°C. 4.0 equiv. (5.52 ml) of a 1.0 molar solution of BBr3 was added slowly via syringe. The reaction was stirred under N2 overnight with concomitant warming to room temperature. 7.0 ml of methanol was added to the reaction mixture and the solvent was removed by rotary vacuum evaporation. The flask was placed under high vacuum (0.05 mm Hg) overnight. The residue was dissolved in water and was carefully neutralized to its free base initially with sodium bicarbonate and finally with ammonium hydroxide (1-2 drops). The free base was isolated by suction filtration and was washed with cold water. The filtrate was extracted several times with dichloromethane and the organic extacts were dried, filtered and concentrated. The filter cake and the organic residue were combined, dissolved in ethanol and carefully acidified with concentrated HCI. After removal of the volatiles, the HCl salt was crystallized as a solvate from methanol in a yield of 0.364 g (81.6%), mp (decomposes i~ 25 195°C). CIMS (isobutane); M + 1 282;'H-NMR (DMSO, HCI salt); d 9.55 (s, 1, NH), 8.85 (s, 1, OH), 8.80 (s, 1, OH), 7.28 (m, 2, ArH), 7.20 (d, 1, ArH), 6.65 (s, 1, ArH), 6.60 (s, 1, ArH), 4.32 (d, 1, ArCH2N), 4.26 (d, 1, ArCHaN), 4.13 (d, 1, Ar2CH, J =11.63 Hz), 2.92 (m, 1, CHN), 2.75 (m, 1, ArCH2), 2.68 (m, 1, ArCH2), 2.29 (s, 3, ArCH3), 2.17 (m, 1, CHZCN), 1.87 (m, 1, CH2CN1.

~",;;.. . . . l .. . . ,. ' ; 5.r. ' ~ . ~.,.~,p-.2:rs;E .-.~H'"
WO 93124462 s~i~ .~ ~ ~ '.~ ~ ~ PCT/US93/0~-"'11 Using the same procedures described in Examples 1-3 above, and those described in U.S. Patent 5,04.7,536, the compounds of Examples 4-35 as set forth in Table I below are synthesized.

iV~ 93/24462 PCY'/U~93/~4971 J ~ ~ :$~
Ri ~- R
b AT BWE

NUMBER

1 ~ H H CH3 H H OH

4 H H CeH~ H H OH

6 C~H, H H CHI H OH

7 H H CaH6 H H OH

8 H H H C2Hs H OH

g H H H CH3 CH3 Br ~ 10 C3H~ H CH3 CH3 H OH

11 CZH6 H H CHa CH3 Br 12 CH3 H H H CzH6 OH

13 C$H9 .H H OH H OH

14 H . H CH3 OH H OH

WO 93/24462 P'CT/US93/0~71 18_ EXAMPLE R R~ R2 R3 R4 X o NUMBER - ~.

16 H H OH H H Br 17 H H Br H H OH

18 H CH3 H Br H , OCH3 19 H CHI H H Br OCH3 20 H CH3 CH3 Br H OCH3 i 23 CH3 H H H F OH

a 27 C3H~ H H CH30 H CI

28 C3H' H H CH3 CH30 CI

30 C3H~ H H H OH OH

35 C~H9 H H CH3 H I

The affinity. for s 1, 2 4 for D-1 the and compounds of Example and D-2 atal homogenates binding sites was assayed utilizing rat brain stri having and D-2 3H-D-1 binding sites labeled with 3H-SCH
23390 and spiperone,respectively.,The dataobtained rexidine in that assay for dihyd and the compounds of Examples 1, 2 and 4 are reported in Table II.

WO 93/244b2 ~ J ~ ~ PCT/US93104971 Exams D-1 D-2 D-1:D-2 Affinity Affinity S_electivity 1 14 nM 650 nM 4S
2 '~ nM 45 nM 6 4 X90 nM 1 S5 nM 0.C
Dihydrexidine S nM 100 nM 13 The compounds of this invention can be formulated in conventional drug dosage forms. Preferred doses of the present compounds depend on many factors, including the indication being treated, the route of administration, and the overall condition of the patient. For oral administration, for example, bffective doses of the present compounds are expected to range from about 0.1 to about 50 mg/kg, more typically about 4.5 to about 25 mg/kg. Effective parenteral doses can range from about 0.01 to about 15 mg/kg of body weight, more typically from about 0.1 to about 5 mg/kg of body weight. In general, treatment regimens utilizing compounds in accordance with the present invention c~mprise administration of from about 1 mg to about 500 mg of the compounds of this invention per day in multiple doses or in a single dose.
Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, and syrups containing inert diluents commonly used in the art, such as water.: Such compositions may also comprise adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, and fiavoring agents. Injectabie preparations of the compounds of the present invention can be formulated utilising art-recognized procedures by dispersing or dissolving an effective dose of the compound in a parenterally acceptable diluent such as water, or more preferably isotonic sodium chloride solution.

WO X3/24462 PGT/US9~/04971 y~ :;~ ~ a The parenteral formulations can be sterilized using art-recognized microfiltration techniques.
The compounds of this invention can also be formulated as solid dosage forms for oral administration such as capsules, tablets, powders, pills and the like. Typically the active compound is admixed with an inert diluent or carrier such as sugar or starch and other excipients appropriate for the dosage form. Thus tabletting formulations will include acceptable lubricants, binders and/or disintegrants. Optionally powder compositions comprising an active compound of this invention and, for example, a starch or sugar carrier can be filled into gelatin capsules for oral administration. Other dosage forms of the compounds of the present invention can be formulated using art-recognized techniques in forms adapted for the specific mode of administration.
The foregoing examples are illustrative of the invention and are not intended to limit the invention to the disclosed compounds. Variations and modifications of the exemplified compounds obvious to one skilled in the art are intended to be within the scope and nature of the invention as specified in the following claims.

Claims (17)

CLAIMS:

1. A compound of the formula or a pharmaceutically acceptable salt thereof wherein H a and H b are trans across ring fusion bond c;
R is hydrogen or C1-C4 alkyl;
R1 is hydrogen or a phenoxy protecting group;
X is a group of the formula -OR5 wherein R5 is hydrogen or a phenoxy protecting group, and providing that the groups R1 and R5 can be taken together to form a group of the formula -CH2-; and R2, R3 and R9 are independently selected from the group consisting of hydrogen, C1-C4 alkyl, phenyl, fluoro, chloro, bromo, iodo, and a group -OR1 wherein R1 is as defined above, provided that at least one of R2, R3 and R4 is other than hydrogen.

2. The compound or salt of claim 1, wherein at least one of the groups R2, R3, and R4 is methyl.

3. The compound or salt of claim 1 or 2, wherein X is hydroxy.

4. The compound or salt of any one of claims 1 to 3, wherein R is hydrogen.

5. The compound or salt of any one of claims 1 to 3, wherein R is C1-C4 alkyl.

6. The compound or salt of any one of claims 1 to 3, wherein R is methyl.

7. The compound or salt of any one of claims 1 to 3, wherein R is n-propyl.

8. The compound or salt of claim 2, wherein R is hydrogen, R2 is methyl, R3 and R4 are hydrogen, R1 is hydrogen and X is hydroxy.

9. The compound or salt of claim 2, wherein R and R1 are hydrogen, X is hydroxy, R3 is methyl and R2 and R4 are hydrogen.

10. The compound or salt of claim 2, wherein R and R1 are hydrogen, X is hydroxy, R4 is methyl and R2 and R3 are hydrogen.

11. A use of a compound or salt of any one of claims 1 to 10, for treating a dopamine-related dysfunction of the central nervous system evidenced by an apparent neurological, psychological, physiological, or behavioral disorder.

12. A use of a compound or salt of any one of claims 1 to 10, in preparing a medicament for treating a dopamine-related dysfunction of the central nervous system evidenced by an apparent neurological, psychological, physiological, or behavioral disorder.

13. A pharmaceutical composition for treating dopamine-related dysfunction of the central nervous system evidenced by an apparent neurological, physiological, psychological, or behavioral disorder, said composition comprising a therapeutically effective amount of the compound or salt according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier therefor.

14. A use of a compound exhibiting selective postsynaptic dopamine D-2 receptor affinity for treating a dopamine-related dysfunction of the central nervous system characterized by an apparent neurological, physiological, psychological, or behavioral disorder, where the compound is of the formula or a pharmaceutically acceptable salt thereof, wherein the H a and H b are trans across ring fusion bond c;
R is hydrogen or C1-C4 alkyl;
R1 is hydrogen or a phenoxy protecting group;
X is a group of the formula -OR5 wherein R5 is hydrogen or a phenoxy protecting group, and providing that the groups R1 and R5 can be taken together to form a group of the formula -CH2-; and R2, R3 and R4 are independently selected from the group consisting of hydrogen, C1-C4 alkyl, phenyl, fluoro, chloro, bromo, iodo, and a group -OR1 wherein R1 is as defined above.

15. The use of claim 14, wherein the compound exhibiting selective postsynaptic dopamine D-2 receptor affinity is a compound of the formula or a pharmaceutically acceptable salt thereof wherein the H a and H b are trans across ring fusion bond c;
R is hydrogen or C1-C4 alkyl;
R1 is hydrogen or a phenoxy protecting group;
X is a group of the formula -OR5 wherein R5 is hydrogen or a phenoxy protecting group, and providing that the groups R1 and R5 can be taken together to form a group of the formula -CH2-; and R2, R3 and R4 are independently selected from the group consisting of hydrogen, C1-C4 alkyl, phenyl, fluoro, chloro, bromo, iodo, and a group -OR1 wherein R1 is as defined above, provided that at least one of R2, R3 and R4 is other than hydrogen.

16. A use of a compound exhibiting selective postsynaptic dopamine D-2 receptor affinity in preparation of a medicament for treating a dopamine-related dysfunction of the central nervous system characterized by an apparent neurological, physiological, psychological, or behavioral disorder, where the compound is of the formula or a pharmaceutically acceptable salt thereof wherein the H a and H b are trans across ring fusion bond c;
R is hydrogen or C1-C4 alkyl;
R1 is hydrogen or a phenoxy protecting group;
X is a group of the formula -OR5 wherein R5 is hydrogen or a phenoxy protecting group, and providing that the groups R1 and R5 can be taken together to form a group of the formula -CH2-; and R2, R3 and R4 are independently selected from the group consisting of hydrogen, C1-C4 alkyl, phenyl, fluoro, chloro, bromo, iodo, and a group -OR1 wherein R1 is as defined above.

17. The use of claim 16, wherein the compound exhibiting selective postsynaptic dopamine D-2 receptor affinity is a compound of the formula or a pharmaceutically acceptable salt thereof wherein the H a and H b are trans across ring fusion bond c;

R is hydrogen or C1-C4 alkyl;

R1 is hydrogen or a phenoxy protecting group;

X is a group of the formula -OR5 wherein R5 is hydrogen or a phenoxy protecting group, and providing that the groups R1 and R5 can be taken together to form a group of the formula -CH2-; and R2, R3 and R4 are independently selected from the group consisting of hydrogen, C1-C4 alkyl, phenyl, fluoro, chloro, bromo, iodo, and a group -OR1 wherein R1 is as defined above, provided that at least one of R2, R3 and R4 is other than hydrogen.