CA1077954A - Benzobicyclononene derivatives - Google Patents

Benzobicyclononene derivatives

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Publication number
CA1077954A
CA1077954A CA251,293A CA251293A CA1077954A CA 1077954 A CA1077954 A CA 1077954A CA 251293 A CA251293 A CA 251293A CA 1077954 A CA1077954 A CA 1077954A
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Canada
Prior art keywords
bicyclo
benzo
nonene
exo
chloro
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Expired
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CA251,293A
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French (fr)
Inventor
Colin L. Hewett
David S. Savage
James Redpath
Thomas Sleigh
Duncan R. Rae
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Akzona Inc
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Akzona Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
    • C07C49/747—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/112—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C07D295/116—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings with the doubly bound oxygen or sulfur atoms directly attached to a carbocyclic ring

Abstract

Abstract of the disclosure The present invention relates to novel benzo(b) bicyclo[3.3.1]nonenes of the general formula I:

I

Description

~77~354 The present invention relates to novel biologically active tri-cyclic compounds, to processes for the preparation of these compounds and to the pharmaceutical application of these compounds. Particularly the invent-ion :relates to novel benzo(b)bicyclo[3.3.1]nonenes of the general formula I:

and a pharmaceutically acceptable acid addition salt or nitrogen oxide there-of, in which Rl and R2 stand for hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, an acyl group or a phenylalkyl group in which the alkyl moiety contains 1 to 6 carbon atoms and in which the phenyl group is unsubstituted or substituted by one or more halogen atoms or lower alkyl or alkoxy groups; R3 represents a free hydroxy group or an etherified or esterified hydroxy group; X and Y are the same or different and represent hydrogen or halogen atoms or alkyl or alkoxy groups of 1 to 6 carbon atoms, nitro, trifluoromethyl or an acyloxy group, or Rl and R2 together with the nitrogen atom represent a 5- or 6-membered heterocyclic ring.
The compounds of the general formula I have valuable biological activities, particularly anorectic activity. Moreover the toxicity of the compounds is very low.
The compounds of the present invention may be prepared accord-ing to the usual methods described in the literature for similar compounds.
Thus this invention also relates to a process for the preparat-ion of a benzo(b)bicyclo~3.3.1]nonene of the general formula I:

D

.. . .
.. . .. . . .. . .
. . . ... : .. . :- .
. . . . .
. -.

-10779~;4 `:or a pharmaceutically acceptable acid addition salt or nitrogen oxide thereof,in which Rl and R2 stand for hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, an acyl group or a phenylalkyl group in which the alkyl moiety contains 1 to 6 carbon atoms and in which the phenyl group is unsubstituted or substituted by one or more halogen atoms or lower alkyl or alkoxy groups; R3 represents a free hydroxy group OT an etherified or esterified hydroxy group; X and Y are the same or different and represent hydrogen or halogen atoms or alkyl or alkoxy groups of 1 to 6 carbon atoms, nitro, trifluoromethyl or an acyloxy group which comprises either:
10 ~a) subjecting a ketone of the general formula II:

~ II
Y

, .
in which R3, X and Y are as previously defined to reductive amination, by reducing the ketone of formula II in the presence of formamide, N-alkylformamide or N,N-dialkylformamide or an amine of the general formula III:

,. ~Rl HN III
\R2 wherein Rl and R2 have the same meanings as Rl and R2 with the exception of an acyl group; or (b) reducing an imine of the general formula IV:

y NR4 IV

., , ~
-27a-.

. .
.

. ' ': - . -: ' ' ~ . ~' ~ - \

1(~77954 in which X, Y and R3 are as previously defined and R4 stands for hydrogen, - hydroxy, Cl 6 alkoxy, Cl 6 alkyl or a phenylalkyl group as defined aboYe; or (c) reacting a reactive derivative of a hydroxyl compound of the general formula V:

~_~ V

.
wherein X and Y are as previously defined and R5 represents an etherified or esterified hydroxy group, with an amine of the general formula III as defined above;
(d) when a compound of formula I is required in which R3 is a hydroxy group hydrolysing a corresponding compound of formula I obtained in which R3 is an etherified or esterified hydroxy group;
~e) when a compound of formula I is required in which one or both of Rl and R2 is a hydrogen atom hydrolysing a corresponding compound of formula I
obtained in which one or both of Rl and R2 is an acyl group;
(f) when a compound of formula I is required in which one or both of R
and R2 is an alkyl group of 1 to 6 carbon atoms, reducing a corresponding compound of formula I obtained in which one or both of R1 and R2 is an alkanoyl group of 1 to 6 carbon atoms;
. (g) wh~n a compound of formula I is required in which R3 is an esterified r hydroxy group esterifying a corresponding compound of formula I obtained in which R3 is a free hydroxy group;
: (h~ when a compound of formula I is required in which one or both of Rl and R2 is an alkyl group of 1 to 6 carbon atoms or an alkenyl group of ~ -2b-, ' ' ~, , ~ ~, , ' .

- 1~77954
2 to 6 carbon atoms, alkylating a corresponding compound of formula I obtained in which one or both of Rl and R2 is a hydrogen atom;
(i) when a compound of formula I is required in which one or both of Rl and R2 is an acyl group, acylating a corresponding compound of formula I
in which one or both of Rl and R2 is a hydrogen atom; and where any one of steps (a) to (i) can be followed by the additional step of converting a base of formula I into a corresponding pharmaceutically acceptable acid addition salt or nitrogen oxide.
A very convenient starting product in the synthesis of the compounds of formula I is a substance of the general formula II:

-2c-~(~779~4 in which X, Y and R3 have the meanings indicated previously.
These compounds II may be prepared in the usual manner starting from an optionally substituted (X and/or Y) ~-tetralone. The tetralone in question, which is commercially available or can be prepared in a convention-al manner from commercially available tetralones, is treated with pyrroli-dine affording the corresponding 2-(pyrrolidino)enamine. The enamine is then converted with acrolein at low temperature into the corresponding 4-hydroxy-benzo(b)bicyclo[3.3.1]nonene-11-one. Alternatively the tetralone in question may be reacted directly with acrolein at elevated temperature in the presence of a tertiary amine such as trimethylamine to gi~e the corres-ponding 4-hydroxy-benzo(b)bicyclo[3.3.1]nonene-11-one directly. The 4-hydroxy group of this compound may then optionally be etherified or esteri-fied. The condensation of the 2-tetralone enamine with acrolein can be - carried out at preferred temperatures from -60 to +25C in a variety of solventsJ but best conditions use a low temperature of -50 to -45 for the addition of acrolein and allow the temperature to increase in a controlled manner to ambient temperature over a period of up to 3 hours.
The alternative direct condensation of the op~ionally substituted (X and/or Y)~ -tetralone with acrolein can be carried out at preferred temperatures between +30 to +120 in a variety of solvents, but preferably at the boiling point of the solvent used, in the presence of a tertiary alkyl amine such as triethylamine or trimethylamine.
Starting from a compound of formula II the amines or amides of ~ the invention I can be prepared most conveniently and directly by a7 reductive amination.
This method involves a reaction of the starting ketone II with formamide, N-alkylformamide or N,N-dialkylformamide or with an amine of the general formula III:

' ' ' : ~ ~ .
' ' ~ ,:
. ~
.~ ~

1077~5~

/ i ~ III
\ R2- -in which Rl and R2 have the same meanings as Rl and R2 with the exception of an acyl group, in the presence of a suitable reducing agent.
A reducing agent, that is very suitable for this reaction, is formic acid or a formic acid derivative such as a salt of formic acid and the amine of formula III. In the latter case the separate addition of the amine III is even superfluous. This reaction may be carried out at elevated temperature, preferably in the range of 80-150C, and most con-veniently at the boiling point of the reaction mixture.
10 Other suitable reducing agents in this reaction are metal hydrides, such as lithiumaluminiumhydride, sodiumborohydride, sodiumtri-methoxyborohydride and diisobutylaluminiumhydride; an alkalimetal, preferably sodium, in an alcohol such as ethanol or isopropanol or hydrogen in the presence of a suitable catalyst, such as Raney nickel, Pt, PtO2, Pd/C etc. Some reducing agents may remove the ether- or the ester group, optionally present at position 4, simultaneously to give compounds with a hydroxy group at position 4, such as LiAlH4.
The compounds of the invention can further be obtained by reduction of the imino moiety of a compound of the general formula IV:

~ NR4 IV
Y

in which X, Y and R3 have the meanings indicated above and R~ stands for hydrogen5 hydroxy, alkoxy, alkyl (1-6 C) or an optionally substituted aralkyl group.

, . .

.

~- 1077954 The compounds of formula IV may be prepared by reaction of the ketone II with a primary amine of formula III (Rl = H) or with hydroxylamine or a hydroxyl-amine-alkylether under alkaline conditions in the usual manner for the preparation of imines or oximes.
The reduction of the imine IV is carried out under mild reaction conditions by means of standard procedures for the reduction of an imino-moiety. For example the reduction can be carried out by hydrogenation in the presence of a suitable catalyst, such as Raney nickel, Pt or PtO2;
with a metalhydride, particularly complex- me~alhydrides derived from aluminium or boron, such as lithium-aluminiumhydride, dissolved or sus-pended in a suitable liquid, such as ether; with an alkalimetal preferably sodium in a suitable liquid such as ether, benzene or alcohol; or with sodiumamalgam or zinc dust in, for example, sodium hydroxide. The reaction may result simultaneously in a splitting off of the 4-ether or the 4-ester group to give the corresponding 4-alcohol, dependent upon the reducing agent used.
A third method for the preparation of the compounds according to the invention is starting from the hydroxyl compound of formula V:
, X ~ OH V
., Y

in which X and Y have the meanings indicated above and R5 represents an etherified or esterified hydroxy group.
` The compound V may be obtained by reduction of the corresponding ketone II under mild conditions so that the R5 group present is not removed. A suitable reducing agent in this respect is sodiumborohydride.
The hydroxyl compound V can be converted into the corresponding amine in various ways. For example, the .
.
'. ' ' .

,' ' ~ ' :
, ~(~77~5~

said hydroxyl group may be converted into a suitable alkyl- or aryl-sulfonyloxy group (leaving group), such as a mesyloxy group, a tosyloxy group, a p-bromophenylsulfonyloxy group, a p-chlorophenylsulfonyloxy group, a p-nitrophenylsulfonyloxy group, etc. and then be reacted with an amine according to the general formula III.
Instead of the conversion of the hydroxyl group into the above-mentioned alkyl- or arylsulfonyloxy group, the hydroxyl group may also be halogenated, for example with PC15, PBr3, SOC12, etc., and then be con-verted into the desired compound I by reaction with the amine III.
; 10 The conversions from a hydroxyl group into an amino group are well-known and described in any chemical textbook.
The aforesaid primary reactions for the preparation of the compounds of the invention (I) may be followed by additional reactions for the conversion of a compound of formula I into a salt or nitrogenoxide thereof, or for the conversion from one compound of the invention into , another compound of the invention.
So, it is possible to modify a substituent present at the phenylnucleus into another substituent within the definition of X and/or ~, Y. For example, a methoxy group may be converted into a hydroxyl group, e.g. by treating with fused pyridine. HCl in the absence of a solvent or by hydrolysis with HBr; a hydroxy group can be converted into an alkoxy ' group, halogen, or an acyloxy group in a conventional manner.
. The amines of the invention, unsubstituted or mono-substituted at the nitrogen atom (Rl and/or R2 is hydrogen) may be ~ar)alkyl-., .

, ~ ' , .' : .

" ' : .

~C~779S4 ated in the usual manner, for example by reacting the compound with an (ar)alkylhalide, or by acylating the compound followed by reduction of the carbonyl group.
For the introduction of methyl-groups at the nitrogen atom the well-known procedure of Eschweiler-Clarke (reaction with formaldehyde +
formic acid) or the reaction with formaldehyde or haloformic esters, followed by reduction with e.g. sodium-cyanoborohydride is to be preferred.
An N-acyl derivative of the compounds according to the invention, may preferably be obtained by acylating a compound I, in which at least one of the groups Rl or R2 is hydrogen, in the usual manner using an anhydri,de or acid halide.
Such acylations, carried out on the 4-alcohol derivative I(in which R3 = OH), will result in simultaneous esterification of the 4-hydroxy group.
Where an N-formyl derivative is obtained directly from one of the aforesaid primary reactions, the amide in question may by hydrolysed using e.g. potassium or sodiumhydroxide to obtain the primary amine I.
Such hydrolysis may result in a simultaneous hydrolysis of the 4-ester group to the 4-alcohol. For example, the reductive amination, in which the ketone II is reacted with formamide in the presence of formic acid (Leuckart-Wallach reaction) gives in first instance the N-formyl de-rivative I, which derivative can be hydrolysed to the primary amine I, or reduced to the corresponding N-methyl compound I.
An O-acyl derivative (R3 = acyloxy) of the compounds according to the invention in which the primary or secondary amine group remains unreacted may be prepared by treating the amine I, in which R3 = OH, with an acylating agent such as an acid halide or anhydride in the presence of a strong acid such as trifluoroacetic acid or perchloric acid.
All these additional conversions which might be carried out '' ' , --, - : :
: :
:

, _ . . ~ !
1(1 77~54 after the aforesaid primary reactions are standard procedures well-known in the art. As far as specific reagents have been mentioned in these additional conversions, it may be understood that these reagents can be replaced by other reagents, well-known in organic chemistry, having a similar effect as the specific reagents described.
The preparation of the ketone II used as starting product in the present synthesis to a compound of formula I results in a mixture consisting , of two enantiomers of formula II in which the 4-alcohol or ester group is in the exo-position, and two enantiomers of formula II in which the 4-alcohol or ester group is in the endo-position. The exo-enantiomers can be separated ,~ from the endo-enantiomers by crystallisation or chromatography. Each of theracemic mixtures II thus obtained may be processed as such and then optionally ;;
resolved after conversion to a racemic compound I or may be resolved and then be processed into an optically active end product according to formula I.
The replacement of the oxo-group at position II of the ketone II
~ with an amino group or the reduction of the imine IV introduces another A asymmetric centre resulting in the mixture of two diastereomers I, in which- the amino group is present in syn- or anti-position with respect to the benzene ring. The separate diastereomeric forms can be isolated from the mixture in the usual manner, for example by column chromatography, preparative thin-layer chromatography and/or fractional crystallisation.
The diastereomers, enantiomers and mixtures thereof of formula I
as well as their preparation are also encompassed by this invention.
The novel compounds of formula I may be isolated from the reaction ` mixture in the form of a pharmaceutically acceptable salt, dependent upon the ~ conditions in which the reaction is carried out. The pharmaceutically accept-: able salts may also be obtained by treating the free base I with an organic or : ~ .

lQ77954 inorganic acid, such as HCl, HBr, Hl, H2S04, H3P04, acetic acid, propionic acid, glycollic acid, maleic acid, malonic acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid, etc.
The term "alkyl" used in the definition of X, Y, Rl and R2 of the general formula I means a saturated branched or unbranched hydrocarbon radical with 1-6 carbon atoms, such as methyl, ethyl, n.propyl, n.butyl, cyclopropyl, cyclopropylmethyl, isopropyl, isobutyl, t.butyl, n.pentyl, iso-pentyl, cyclopentyl and hexyl. The same applies to the alkyl group present in the term "alkoxy" used in the definition of X and Y.
The term "alkenyl" used in the definition of Rl and R2 of the general formula I means an unsaturated branched or unbranched hydrocarbon radical with 2-6 carbon atoms such as vinyl, allyl and 3-methyl-but-2-enyl.
By "halogen" is preferably meant chlorine or bromine.
By an "aralkyl~group", mentioned in the definition of Rl and R2, is meant an alkyl group with 1-6 carbon atoms, substituted with at least one aromatic group. Preferably a phenylalkyl group is meant, in which the alkyl group has 1-4 carbon atoms and in which the phenyl group may be substituted by one or more halogen, lower alkyl or alkoxy groups (1-4 C), such as benzyl, phenyl-ethyl, phenylpropyl, phenylbutyl, l-methyl-l-phenyl-ethyl, o-, m-, or p-anisyl, o-, m- or p-chloro-benzyl, veratryl, o-, m- or p-methyl-phenethyl or o-, m- or p-hydroxyphenethyl.
An "acyl group" mentioned in the definition of Rl, and R2 means a group derived from an aliphatic, araliphatic or aromatic carboxylic acid.
The aliphatic carboxylic acids cover acids with 1-18 carbon atoms, in-cluding a carbocyclic ring, and particularly those with 1-8 carbon atoms, such as acetic acid, propionic acid, butyric acid, iso-butyric acid, valeric acid, hexanoic acid, heptanoic acld, trimethyl-acetic acid, cyclopentane-or cyclohexane-carboxylic acid. The araliphatic or aromatic carboxylic ~, acids cover unsubstituted as well as substituted araliphatic ., _ 9 _ .. . . . . . .
.
.
.

` 1~77954 or aromatic carboxylic acids with 1-18 carbon atoms, especially the optionally substituted phenyl-carboxylic acids, and optionally substituted phenylalkyl-carboxylic acids) in which the alkyl group contains 1-4 carbon atoms and may be saturated as well as unsaturated, such as benzoic acid, o-, m- or p-toluic acid, o- or p-chlorobenzoic acid, p-methoxybenzoic acid, phenyl acetic acid, phenylpropionic acid, cinnamic acid, phenylbutyric acid, p-methylphenyl acetic acid, p-nitrobenzoic acid, etc.
The acyl group in the term "acyloxy" or "esterified hydroxy group"
used in the definitions of X, Y and R3 has a similar meaning.
The etherified hydroxy group mentioned in the definition of R3 is an aliphatic (1-6 C) ether, a cycloaliphatic (5-10 C) ether, an aromatic ether, preferably a phenyl-ether, an araliphatic ether, preferably a phenyl-alkylether, or a heterocyclic ether such as a tetrahydropyranylether. The phenyl moiety in the phenyl or phenylalkyl ethers may be substituted by alkyl (1-4 C), alkoxy ~1-4 C), halogen or nitro.
The heterocyclic five- or six-membered rings, as mentioned in the definition of Rl and R2 (together with the nitrogen atom), are derived from 5- or 6-membered cyclic amines of formula III, such as pyrrole, pyrrolidine, pyrroline, piperidine, piperazine, imidazole or morpholine.
The nitrogen oxides of the compounds of the invention are prepared by oxidising a compound I with H2O2 or a peracid.
The novel compounds according to this invention as well as the pharmaceutically acceptable salts thereof have, as already said, valuable anorectic activities. A long term oral administration of the compounds I
did not evoke tolerance to the anorectic effect. The compounds I, especially the ll-syn isomers I, show moreover a moderate 1~77954 ., anti-inflammatory activity. Purthermore an antidepressant effect is indicated by the overall pharmacological profile of the compounds of the invention.
The compounds of the invention may be administered orally, parenterally and locally (the latter substantially for anti-inflammatory purposes), in a daily dosage of from 0.005 to 50 mg, preferably 0.01-10 mg, per kg body weight.
Mixed with suitable auxiliaries the compounds I may be compressed into solid dosage units, such as pills, tablets and coated tablets or be processed into capsules.
By means of suitable liquids the compounds I can also be applied as an injection preparation in the form of solutions, suspensions or emulsions.
For topical administration the compounds may also be processed into a cream or ointment.
Preferred compounds of the invention are compounds of formula I, in which Rl and R2 are hydrogen or methyl and/or the benzonucleus has been substituted by one or two halogen and/or R3 stands for hydrogen, a lower aliphatic acyl group (1-8 C) or a lower araliphatic acyl group, such as benzOyl~

.' ,~.

.. ... .
., - 11 -.,.

- , . . . . . .:
, : , : .

: .
~:
, ' '' ''' ' ~ ~ ' .': ' .. . . . .

: 1~77954 STARTING PRODUCTS
The preparation of 4-exo and 4-endo-hydroxy as well as 4-exo- and 4-endo-benzyloxy-8-chloro-benzo(b)bicyclo[3.3.1] nonen-ll-one is described starting from 6-chloro-2-tetralone. Other starting products according to formula II are prepared in a similar manner.
A. 6-chloro-2- tetralone pyrrolidine enamine A solut;on of 6-chloro-2-tetralone (260 g) in benzene (1.5 1) and pyrrolidine (208 ml) was refluxed under nitrogen for 2.5 h using a Dean and Stark water separator to collect the water formed. The reaction mixture was evaporated to dryness under reduced pressure, venting with nitrogen at the end of the distillation. The residue was triturated with hexane to give 6-chloro-2-tetralone pyrrolidine-enamine (276 g; 82%) m.p. 121-122C.
B. 8-chloro-4-hydroxy=benzo(b)bicyclo[3.3.1]nonen-11-one B.l. 6-chloro-2-tetralone pyrrolidine enamine (390 g) was added portionwise during 10 min. to a stirred solution of acrolein (214 ml) in methylene dichloride (3.0 1) cooled to -50 to -55C. The reaction mixture was stirred for 30 min. at -50 to -55C, then the temperature was allowed to rise to +5 during 3 h. Water (420 ml) was added, followed by 5N hydrochloric acid (400 ml) and the resulting biphase mixture was stirred at room temperature for 2 h and set aside overnight.
The layers were separated and the aqueous layer was extracted with methylene dichloride. The methylene dichloride extracts were washed with lN hydrochloric acid, aqueous brine, dried and evaporated to dryness to give a mixture (approx. 60:40) of 8-chloro-4-exo- and 8-chloro-4-endo-hydroxy-benzo(b)bicyclo~3.3.1]nonen-11-one as an oil (371 g).
B.2. Acrolein (389 ml) was added to a stirred solution of 6-chloro-- ,.
- .

- , : . - :
: , '. : ' ` 10~7954 2-tetralone (738 g) in tetrahydrofuran (738 ml) and triethylamine (738 ml) under a nitrogen atmosphere and the mixture was heated under reflux for 2.5 h. The solvents were distilled off in vacuo and the triethylamine finally removed by azeotropic distillation with toluene (2.75 1) in portions (250 ml).
; The crude ketol mixture (810 g) was dissolved in toluene, filtered through alumina, and the eluate evaporated to give a mixture (approx. 60:40) of 8-chloro-4-exo- and 8-chloro-4-endo-hydroxy-benzo(b)bicyclo[3.3.1]nonen-11-one as an oil (792 g).
C 4-Exo- and 4-endo-benzoyloxy-8-chloro-benzo(b)bicyclo[3.3.1]nonen-11-one .

A solution of 8-chloro-4-exo- and 8-chloro-4-endo-hydroxy-benzo(b) ; bicyclo[3.3.1]nonen-11-one (52 g) in pyridine (104 ml) was cooled with stirring to 2 and benzoyl chloride (30.5 ml) was added dropwise, keeping the temperature below 10C. Stirring was continued at 5 to 10C for
3.5 h. Water was added to the cooled, stirred mixture to precipitate the product, which was dissolved in methylene dichloride and washed with 2N
hydrochloric acid, water to pH 7, dried, and evaporated to give a mixture of 4-exo- and 4-endo-benzoyloxy-8-chloro-benzo(b)bicyclo[3.3.1]nonen-11-one (62 g) (approx. 60:40).
" 20 A solution of the product in methylene dichloride was filtered through a column of alumina, concentrated, and the residue crystallised from methylene dichloride-cyclo-hexane to give pure 4-exo-benzoyloxy-8-chloro-benzo(b)bicyclo[3.3.1]nonen-11-one (26 g) m.p. 184-186C. The mother liquor was chromatographed over alumina to give a further quantity (7.5 g) of pure 4-exo-benzoyloxy-8-chloro-benzo(b)bicyclo[3.3.1]nonen-11-one and ~ pure 4-endo-benzoyloxy-8-chloro-benzo(b)bicyclo[3.3.1]nonen-11-one (18.5 .~
g) m.p. 120-122C.

, "

.
:' ' . ' :, :

1(~77954 EXAMPLE I
4-exo-Benzoyloxy-8-chloro-11-anti-formamido-~enzo(b)bicyclo[3.3.1]nonene.
A suspension of 4-exo-benzoyloxy-8-chloro-benzo(b)bicyclo[3.3.1]nonen-11-one (33.5 g) in a mixture of formamide (134 ml) and formic acid (67 ml) is boiled under reflux for 2.5 h. After cooling the mixture, water is added and the solid is filtered off, washed with water and dried (32.5 g). The product is crystallised from methylene dichloride/methanol giving 4-exo-benzoyloxy-8-chloro-11-anti-formamido-benzo(b)bicyclo~3.3.1]nonene as prisms (28.5 g) m.p. 224-226C.
EXA~lPLE II
4-endo-Benzoyloxy-8-chloro-11-formamido-benzo(b)bicyclo[3.3.1]nonene.
A stirred suspension of 4-endo-benzoyloxy-8-chloro-benzo(b)bicyclo[3.3.1]
nonen-ll-one (18.5 g) in a mixture of formamide (74 ml) and formic acid (37 ml) is heated under reflux for 2.5 h. After cooling the mixture, water is added and the gum is dissolved in methylene dichloride, washed neutral and chromatographed over silica gel to give 4-endo-benzoyloxy-8-chloro-ll-anti-formamido-benzo(b)bicyclo[3.3.1]nonene (7 g) as prisms m.p. 150-152 and 4-endo-benzoyloxy-8-chloro-11-synformamido-benzo(b)bicyclo[3.3.1]nonene as an almost colourless gum (3.5 g).
EXAMPLE III
4-Acetoxy- or 4-benzoyloxy-11-formamido-substituted benzo(b)bicyclo[3.3.1]
.
nonene Starting from the desired 4-acyloxy-benzo(b)bicyclo[3.3.1]nonen-11-one compound, unsubstituted or substituted at the benzo ring, the following ll-formamido compounds are prepared in the same manner as described in Examples I and II.
4-exo-Acetoxy-8-methoxy-11-anti-formamido-benzo(b)bicyclo[3.3.1]nonene, m.p. 172-173C;

.

. ~: . - - ,, : .

- , . -. . : : ' :

~ 77954 4-exo-Benzoyloxy-8-bromo-ll-antl-formamido-benzo(b)bicyclo [3.3.1]nonene, m.p. 229-230C;

- 14a -- - . ~, : :

' .

. . . :
. ~

'` 10779S4 :
4-endo-Benzoyloxy-8-bromo-11-anti-formamido-benzo(b)bicyclo[3.3.1]nonene, (oil) 4-exo-Benzoyloxy-8,9-dichloro~ anti-formamido-benzo(b)bicyclo[3.3.1]nonene, m.p. 242-243C;
4-endo-p.nitrobenzoyloxy-9-chloro-11-anti-formamido-benzo~b)bicyclo[3.3.1]
nonene, m.p. 142-149C;
4-endo-p.nitrobenzoyloxy-9-chloro-11-syn-formamido-benzo~b)bicyclo[3.3.1]nonene, m.p. 197-200C;
4-exo-Acetoxy-ll-anti-formamido-benzo(b)bicyclo[3.3.1]nonene, m.p. 121-122C;
4-exo-Acetoxy-ll-syn-formamido-benzo(b)-bicyclo[3.3.1]nonene, m.p. 182-184C;
4-exo-Acetoxy-8-chloro-9-CF3-11-anti-formamido-benzo(b)bicyclo[3.3.1]nonene.
EXAMPLE IV
4-e~ ~y~ y _____ oro-11-anti-amino-ben ~ l33 ~
A suspension of 4-exo-benzoyloxy-8-chloro-11-anti-formamido-benzo(b)bicyclo-[3.3.1]nonene (8 g)in ethanol (80 ml) and lOM potassium hydroxide solution (14 ml) is heated under reflux for 4 h during which time a solution is obtained. After cooling, aqueous brine is added to precipitate the amine which is filtered off, washed with water and dried to give 4-exo-hydroxy-8-chloro-ll-anti-amino-benzo(b)bicyclo[3.3.1]nonene as prisms (5 g). The amine ~4.3 g) is dissolved in ethanol/toluene and converted to the hydrochloride '~ 20 by addition of a solution of hydrogen chloride gas in ether. Crystallisation from isopropanol gives pure 4-exo-hydroxy-8-chloro-11-anti-amino-benzo(b)-bicyclo[3.3.1]nonene hydrochloride (4.1 g) m.p. 182-194 (decomp.).

In the same manner are prepared:
4-exo-hydroxy-8-methoxy-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene.HCl~
identical with the product obtained in Example XlX
4-exo~hydroxy-8-bromo-11-anti-amino-benzo(b)bicyclo[3~3.1]nonene.HCl.

~ ~ -15-. ~ .

, .
, - , . ..

, ' ' , ' ' , 1~77gS4 4-endo-hydroxy-8-bromo-11-anti-amino-benzo(b)bicyclo[3.3.1]noneneOHCl.
4-exo-hydroxy-8,9-dichloro-11-anti-amino-benzo~b)bicyclo[3.3.1]nonene.HCl, identical with the product obtained in Example XlXo 4-endo-hydroxy-8,9-dichloro-11-anti-amino-benzo(b)bicyclo[3.3O1]nonene.HCl.
4-endo-hydroxy-8,9-dichloro-11-syn-amino-benzo(b)bicyclo[3O3O1]nonene.HCl.
4-exo-hydroxy-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene.HCl, identical with the product obtained in Example XlX;
4-exo-hydroxy-8-methyl-11-anti-amino-benzo(b)bicyclo[3.3.1]noneneOHC10 4-exo-hydroxy-8-chloro-9-CF3-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene oHCl 4-exo-hydroxy-8-nitro-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene. HC 1 : EXAMPLE V
4-hydroxy-8-chloro-11-methylamino-benzo(b)bicyclo~3.3.11nonene HCl A solution of 4-exo-benzoyloxy-8-chloro-11-anti-formamido-benzo(b)bicyclo-~3.3.1]nonene (7O25 g) in dry tetrahydrofuran ~110 ml) is added dropwise to a stirred suspension of lithium aluminium hydride (2.0 g) in dry tetrahydrofuran ~40 ml) and the mixture is stirred under reflux for 5 h.
After the addition of water, the inorganic solids are filtered off. The filtrate is concentrated, toluene added and the solution is evaporated in vacuo to give 4-exo-hydroxy-8-chloro-11-anti-methylamino-benzo(b)bicyclo[3.3.1]-nonene ~6.5 g) as a gum, which is dissolved in methylene dichloride and converted to the hydrochloride by addition of a saturated solution of hydrogen chloride gas in ether. Crystallisation from methylene dichloride/ethyl acetate gives pure 4-exo-hydroxy-8-chloro-11-anti-methylamino-benzo(b)bicyclo-~3.3.1]nonene hydrochloride as prisms (4.2 g) mOp.~'190C ~decomp.).
.

~ -16-..

. . . .

,' :
.

1~77954 In the same manner 4-endo-hydroxy-8-chloro~ anti-methylamino-benzo~b)bicyclo[3.3.1]nonene hydrochloride, m.p. 262-268 and 4-endo-hydroxy-8-chloro-11-syn-methylamino-benzo~b)bicyclo[3.3.1]nonene hydrochloride are prepared starting from the appropriate 4-endo-acetoxy- or benzoyloxy-ll-formamido compounds.
EXAMPLE VI
4-Hydroxy-ll-methylamino-substituted-benzo~b)bicyclo[3.3.1]nonene.
Starting from the desired 4-acetoxy- or 4-benzoyloxy-11-formamido-benzo(b) - bicyclo[3.3.1]nonene, unsubstituted at the phenyl ring, or substituted at the phenyl ring with 9-chloro, 8-methoxy, 8-hydroxy, 8-methyl, 8,9-dichloro or 8-chloro-9-nitro respectively, the following ll-methylamino compounds are prepared in the same manner as described in Example V.
4-exo-Hydroxy-ll-anti-methylamino-benzo~b)bicyclo[3.3.1]nonene.
4-endo-Hydroxy-ll-anti-methylamino-benzo~b)bicyclo[3.3.1]nonene.
4-exo-Hydroxy-8-methoxy-11-anti-methylamino-benzo(b)bicyclo[3.3.1]nonene.
4-endo-Hydroxy-8-methoxy-11-anti-methylamino-benzo~b)bicyclo[3.3.1]nonene.
4-endo-Hydroxy-8-methoxy-11-syn-methylamino-benzo~b)bicyclo[3.3.1]nonene.
4~endo),8-Dihydroxy-ll-anti-methylamino-benzo~b)bicyclo[3.3.1]nonene.
4-exo-Hydroxy-8-methyl-11-anti-methylamino-benzo(b)bicyclo[3.3.1]nonene.
4-eXo-Hydroxy-8,9-dichloro-ll-anti-mèthylamino-benzo(b)bicyclo[3.3.1]nonene.
4-exo-Hydroxy- 9-chloro- 11-anti-methylamino-benzo~b)bicyclo[3.3.1]nonene.
4-exo-Hydroxy-8-chloro-9-nitro-11-anti-methylamino-benzo~b)bicyclo[3.3.1]
nonene.

- ' ', - . . .
. .
. . .
. . . . ..
' ~
, :..

EXAMPLE VII
8-Bromo-4-exo-hydroxy~ anti-methylamino-benzo~b)bicyclo[3.3.1]nonene.HCl.
A mixture of 4-exo-benzoyloxy-8-bromo-benzo(b)bicyclo[3.3.1]nonen-11-one (6 g) and N-methyl-formamide ~18 ml) in formic acid (9 ml) is boiled under reflux for 3 h. The reaction mixture is cooled to room temperature, diluted with water and treated with 2N sodium hydroxide solution to give a yellow gum, which is extracted with methylene dichloride. The methylene dichloride extracts were washed with water, dried and evaporated to give a brown gum (5.97 g). The gum (5.97 g) is dissolved in ethanol (120 ml) and heated under reflux with lON potassium hydroxide solution (12 ml) for 27 h. The reaction mixture is cooled to room temperature, diluted with brine and extracted with methylene dichloride. The methylene dichloride extracts are washed with water, dried and evaporated in vacuo to give the crude amine as an orange gum (4.23 g), which is dissolved in methylene dichloride and con-verted to the hydrochloride by addition of a solution of hydrogen chloride gas in ether. Crystallisation from methylene chloride and from methanol-ether gives pure 4-exo-hydroxy-8-bromo-11-anti-methylamino-benzo(b)bicyclo [3.3.1]nonene hydrochloride as colourless crystals (1.30 g), m.p. 264-270C.
EXAMPLE VIII
4-exo-acetoxy-8-chloro-11-anti-methylamino-benzo(b)bicyclo[3.3.1]nonene.HCl.
A solution of 4-exo-hydroxy-8-chloro-11-anti-methylamino-benzo(b)bicyclo [3.3.1]nonene (4 g) in a mixture of perchloric acid (6 ml), acetic anhydride (10 ml) and glacial acetic acid (20 ml) is set aside for 1 h. The solution is poured into ice-water, solid potassium carbonate added until alkaline and the product is extracted into methylene dichloride, washed to neutrality, dried and evaporated to dryness to give 4-exo-acetoxy-8-chloro-11-anti-methylamino-benzo(b)bicyclo[3.3.1]nonene (4.7 g) as a gum. The product is dis-. .

7795~

solved in methylene dichloride and filtered through acid-washed alumina.
The eluate is concentrated and a saturated solution of hydrogen chloride gas in ether is added to precipitate the hydrochloride (3.65 g), crystallisation of which from methanol-ethyl acetate yields 4-exo-acetoxy-8-chloro-11-anti-methylamino-benzo(b)bicyclo[3.3.1]nonene hydrochloride as prisms (3.1 g) m.p.

?56C.
In a similar manner the following compounds are prepared:
4-exo-acetoxy-8-chloro-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene.HCl, m.p. 256C;
4-endo-acetoxy-8-chloro-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene.HCl, m.p. 259-263C;
4-exo-acetoxy-8,9-dichloro-11-anti-methylamino-benzo(b)bicyclo[3.3.1]nonene.
HCl, m.p. 247-253C.
EXAMPLE IX
4-exo-benzoyloxy-8-chloro-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene.HCl.
Benzoyl chloride (2.3 ml) is added dropwise to a solution of 4-exo-hydroxy-8-chloro-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene (4.8 g) in trifluoro-acetic acid (20 ml) and the mixture is stirred at room temperature for 7 h.
then poured on to ice. Solid sodium carbonate is added until alkaline and the product is extracted into ethyl acetate. The extract is washed with 2 M NaOH, and water to pH 7, then dried and evaporated to give a gum (5.0 g). Crystallisation from ether gives 4-exo-benzoyloxy-8-chloro-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene (3.2 g).
Treatment of the crystalline product in methylene dichloride with a saturated solution of hydrogen chloride gas in ether gives 4-exo-benzoyl-oxy-8-chloro-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene.HCl, m.p. 213-220C.

_ 19 -'' . ~ ~ . .: ~

: . . , ' : . ~ : - .
'' ' ' ': ' ,: ' ~

`

EXAMPLE X
~ y treatment of the 4-hydroxy-ll-amino- and ll-methylamino compounds with the appropriate acylhalide, the following compounds are prepared in a manner, similar to that described in example IX.
4-exo-benzoyloxy-8-chloro-11-anti-methylamino-benzo(b)bicyclo[3.3.1]nonene.
I~Cl 4-exo(2,2-dimethylpropionyloxy)-8-chloro-ll-anti-amino-benzo(b)bicyclo [3.3.1]nonene.HCl.
4-endo-benzoyloxy-8-methoxy-11-syn-methylamino-benzo(b)bicyclo[3.3.1]nonene.
HCl.
4-exo-benzoyloxy-8-bromo-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene.HCl.
EXAMPLE XI
4-exo-hydroxy-8,9-dichloro-11-anti-dimethylamino-benzo~b)bicyclo[3.3.1]
nonene.HCl A solution of 4-exo-hydroxy-8,9-dichloro-ll-anti-amino-benzo(b) bicyclo[3.3.1]nonene (16.6 g) in a mixture of formic acid (16.6 ml) and formalin (15.5 ml) is boiled under reflux for 2 h., diluted with water and an excess of potassium hydrogen carbonate solution and extracted with methylene dichloride. The extract is washed neutral with water, dried and evaporated and the residue crystallised from ether to give 4-exo-hydroxy-8,9-dichloro-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene (16.2 g), m.p. 133.5-135. The product is dissolved in methylene chloride and treated with a solution of hydrogen chloride in ether to give the hydrochloride, m.p. 248-273C.
The same compound is obtained by refluxing a mixture of 4-exo-benzoyloxy-8,9-dichloro-benzo(b)bicyclo[3.3.1]nonen-11-one and dimethyl-formamide in formic acid in a similar manner as described in Example VII.

1~77gS4 EXAMPLE XII
4-Hydroxy~ dimethylamino-benzo(b~bicyclo[3.3.1]nonenes.
Starting from the desired 4-hydroxy-11-amino-benzo(b)bicyclo [3.3.1lnonene, unsubstituted at the phenyl ring, or substituted at the phenyl ring with 8,9-dichloro, 8-methoxy, 8-hydroxy, 9-chloro, 8-chloro and 8,10-dichloro respectively, the ollowing ll-dimethylamino compounds are prepared in the manner described above.
4-exo-hydroxy-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene.HCl, 4-exo-hydroxy-8-methoxy-11-anti-dimethylamino-benzo(b)bicycle[3.3.1]nonene.
HCl, 4-endo-hydroxy-8,9-dichloro-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1]
nonene.HCl, 4-endo-hydroxy-8,9-dichloro-11-syn-dimethylamino-benzo(b)bicyclo[3.3.1]nonene.
HCl, 4(exo),8-dihydroxy-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene.HCl, 4-exo-hydroxy-8-chloro-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene.HCl, 4-endo-hydroxy-8-chloro-11-anti-dimethylamino-benzo(b)bicycloE3.3.1]nonene.
HCl, 4-endo-hydroxy-8-chloro-11-syn-dimethylamino-benzo(b)bicyclo[3.3,1]nonene.HCl, 4-exo-hydroxy-9-chloro-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene.HCl, 4-exo-hydroxy-8,10-dichloro-11-syn-dimethylamino-benzo(b)bicyclo[3.3.1]
nonene.HCl, E MPLE XIII
4-exo-Acetoxy-8,9-dichloro-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1]
nonene.HCl.
Acetylation of 4-exo-hydroxy-8,9-dichloro-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene (4.0 g) with acetic anhydride (8 ml) and pyridine (8 ml) at room temperature gives 4-exo-acetoxy-8,9-dichloro-11-anti-. ' ' . ' '. ..
- ~ .
. . , . ~ - .
.
~

1~377954 dimethylamino-benzo(b)bicyclo[3.3.1]nonene (4.4 g), m.p. 122.5-124. This is dissolved in methylene chloride and treated with a solution of hydrogen chloride in ether to give the hydrochloride, m.p. 234-27~.
The following compounds are acylated in a similar manner 4-endo-acetoxy-8,9-dichloro-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1]
nonene.HCl, 4-exo-phenylacetoxy-8,9-dichloro-11-anti-dimethylamino-benzo(b~bicyclo[3.3.1]

nonene . HC 1, 4-exo-benzoyloxy-8,9-dichloro-11-anti-dimethylamino-benzo(b)bicyclol3.3.1]
nonene.HCl, 4-exo-heptanoyloxy-8,9-dichloro-11-anti-dimethylamino-benzo(b)bicyclol3.3.1]
nonene.HCl, 4-exo-(2,2-dimethylpropionyloxy)-8,9-dichloro-11-anti-dimethylamino-benzo(b) bicyclo[3.3.1]nonene.HCl.
EXAMPLE XIV
Esters of 4-hydroxy-11-dimethylam no-benzo(b)bicyclo[3.3.1]nonene derivatives.
Starting from the desired 4-hydroxy-11-dimethylamino-benzo(b) bicyclo[3.3.1]nonene, unsubstituted at the phenyl ring, or substituted at the phenyl ring with 8-methoxy, 8-bromo, 8-chloro and 8-methyl respectively, the following esters of 4-hydroxy-11-dimethylamino compounds are prepared in the manner described above.
4-exo-acetoxy-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1] nonene.HCl.
4-exo-benzoyloxy-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene.HCl.
4-exo-(2,2-dimethylpropionyloxy)-11-anti-dimethylamino-benzo(b)bicyclo 13.3.1]nonene.HCl.
4-exo-(1-phenylpropionyloxy)-11-anti-dimethylamino-benzo(b)bicyclo~3.3.1]
nonenc.HCl.
4-cxo-cinnamoyloxy-11-anti-dimethylamino-benzo(b)bicyclo~3.3.1]nonene,HCl.

- 1~779S4 4-exo-decanoyloxy-ll-anti-dimethylamino-benæo(b)bicyclo[3.301]nonene.HCl.
4-exo-~lcetox~-8-bromo-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene.HCl.
4-endo--benzoyloxy-8-chloro-ll-syn-dimethylamino-benzo(b)bicyclo[3.301]nonene.
HCl.
4-exo-~2,2-dimethylpropionyloxy)-8-chloro-11-anti-dimethylamino-benzo(b) bicyclo[30301]nonene.HCl.
4-endo-benzoyloxy-8-chloro~ anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene.
HCl.
4-exo-acetoxy-8-chloro-11-anti-dimethylamino-benzo(b)bicyclo[3.3~1]nonene.HCl.
4-exo-benzoyloxy-8-chloro-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene.
HCl.
EXAMPLE_XV
4-exo-acetoxy-ll-anti-acetamido-benzo(b)bicyclo[3-~3-~l~noneneo 4-exo-hydroxy-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene (20 g) is suspended in acetic anhydride (40 ml) and the mixture stirred at room temperature for 1 hour, and then poured into water. The solid is collected and dried to give 4-exo-acetoxy-ll-anti-acetamido-benzo(b)bicyclo[303,1]
nonene (12.6 g), m.p. 213-214.
In the same manner is prepared with (phenyl)propionylchloride;
4-exo-phenylpropionyloxy-11-anti-phenylpropionylamido-benzo(b)bicyclo[3.3.1]
nonene, 4-exo-propionyloxy-11-anti-propionylamido-benzo(b)bicyclo[3~3.1]nonene.
A stirred suspension of 4-exo-benzoyloxy-8-chloro-11-anti-amino-benzo(b)bicyclo~3,3.1]nonene in acetic anhydride r0sults in the same manner as described above in 4-exo-benzoyloxy-8-chloro-11-anti-acetamido-benzo~b) bicyclo[3.3.1]nonene, identical with the product obtained in Example Xl.
A stirred mixture of 4-exo-benzoyloxy-8-chloro-11-anti-. . ~ ., ~ ) ~i -23-.... , ~

: .

1C~77954 amino-benzo(b)bicyclo[3.3.1]nonene and benzoyl-chloride in toluene results in: 4--exo-benzoyloxy-8-chloro-11-anti-benzoylamldo-benzo~b)bicyclo[3.3.1]
nonene.
EXAMPLE XVI
4-exo-hydroxy-11-anti-ethylamino-benzoCb)bicyclo[3.3.1]nonene.HCl.
-To a suspension of LiAlH4 (3.3 g) in dry tetrahydrofuran is addeda hot suspension of 4-exo-acetoxy-11-anti-acetamido-benzo(b)bicyclo[3.3.1]
nonene (12.5 g) in a mixture of tetrahydrofuran and dioxan (300 ml) and the mixture refluxed for 2 hours. The excess lithium aluminium hydride is destroyed by the addition of water, the mixture filtered and the filtrate evaporated to dryness. The residue is dissolved in ether, treated with a saturated solution of hydrogen chloride in ether and the solid formed is recrystallised from methane-ether to give 4-exo-hydroxy-11-anti-ethylamino-benzo(b)bicyclo[3.3.1]nonene hydrochloride (12 g), m.p. > 265.
In the same manner is prepared:
4-exo-hydroxy-11-anti-phenylpropylamino-benzo(b)bicyclo[3.3.1]nonene.HCl, 4-exo-hydroxy-11-anti-propylamino-benzo(b)bicyclo[3.3.1]nonene, 4-exo-hydroxy-8-chloro-11-anti-ethylamino-benzo(b)bicyclo[3.3.1]nonene, 4-exo-hydroxy-8-chloro-11-anti-cyclopropyllmethylamino-benzo(b)bicyclo [3.3.1]nonene, 4-exo-hydroxy-8-chloro-11-anti-p-hydroxyphenethylamino-benzo(b)bicyclo [3.3.1]nonene.
EXAMPLE XVII
4-exo-Hydroxy-ll-anti-N-methyl-N-(3-methyl-but-2-enyl)-amino-benzo(b) bicyclo[3.3.1]nonene hydrochloride.
To a stirred suspension of 4-exo-hydroxy-11-anti-methylamino-benzo(b)bicyclo[3.3.1]nonene (5.5 g) and potassium bicarbonate (5.0 g) in dimethyl formamide (10 ml) and methylene chloride (1 ml) is added _ 24 -1~77~54 dropwise a solution of l-bromo-3-methyl-but-2-ene (5.5 ml) in dimethyl formamide (10 ml) whilst maintaining the mixture at room temperature.
The reaction mixture is stirred for a further 15 minutes and then poured into water. The product is extracted with methylene dichloride. The extract is washed with water, dried and evaporated to give an oil, which is chromatographed on alumina. Elution with benzene gives an oil (5 g) which is dissolved in ether and treated with a saturated solution of hydrogen chloride in ether. The solid formed is recrystallised from methanol-ether to give 4-exo-hydroxy-11-anti-N-methyl-N-(3-methyl-but-2-enyl)-amino-benzo(b) bicyclo[3.3.1]nonene hydrochloride (3.1 g), m.p. 258-259.
EXAMPLE XVIII
In an analogous manner as described in Example I various benzo(b) bicyclo[3.3.1]nonene derivatives are prepared by reacting 4-exo-benzoyloxy-8-chloro-benzo(b)bicyclo[3.3.1]nonen-11-one with the desired amine of formula III in the presence of formic acid or with the amine salt of formic acid, whether or not dissolved in a suitable inert solvent. In this manner are prepared:
4-exo-benzoyl-8-chloro~ anti-morpholino-benzo(b)bicyclo[3.3.1]nonene, 4-exo-benzoyl-8-chloro-11-anti-piperidino-benzo(b)bicyclo[3.3.1]nonene, 4-exo-benzoyl-8-chloro-11-anti-pyrrolidino-benzo(b)bicyclo[3.3.1]nonene.
EXAMPLE XIX
Various 4-hydroxy-benzo(b)bicyclo[3.3.1]nonene-11-oxime derivatives are reduced with sodium in isopropanol to give the corresponding primary amines I. The oximes are obtained by reaction o~ 4-(endo or exo)-benzoyloxy-benzo(b)bicyclo[3.3.1]nonen-11-one derivatives with hydroxylamine.HCl in sodium hydroxide and ethanol. The following compounds are prepared:
4-exo-hydroxy-8-methoxy-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene.HCl, m.p. 256-258~C, .; .

: -1~77~54 4-exo-hydroxy-8,9-dichloro-11-anti-amino-benzo(b~bicyclo~3.3.1]nonene.HCl, m.p. 286-300C, 4-exo-hydroxy-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene.HCl, sublimation 265C.
EXAMPLE XX
In the same manner as described in Example I the following com-pounds are prepared by refluxing the appropriate starting ketone in a mixture of formic acid and formamide or dimethylformamide respectively:
4-exo-p.nitrobenzoyloxy-9-chloro-11-anti-formamido-benzo(b)bicyclo[3.3.1]
nonene.HCl, m.p. 269-272C;
4-exo-p.nitrobenzoyloxy-8-nitro-9-chloro-ll-anti-formamido-benzo(b)bicyclo [3.3.1]nonene.HCl, m.p. 276-279 (dec.);
4-exo-p.nitrobenzoyloxy-9-chloro-10-nitro-11-anti-formamido-benzo(b)bicyclo [3.3.1]nonene.HCl, m.p. 253-262C (dec.);
4-endo-p.nitrobenzoyloxy-8-nitro-9-chloro-11-anti-formamido-benzo(b)bicyclo [3.3.1]nonene.HCl, m.p. 229-231C;
4-exo-hydroxy-8-chloro-9-nitro-11-anti-formamido-benzo(b)bicyclo[3.3.1]nonene.
HCl, m.p. 248C;
4-exo-methoxy-8-chloro-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene, (oil);
4-exo-hydroxy-8-t.butyl-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene (oil);
4-exo-decanoyloxy-8-chloro-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1 nonene, HCl.

Claims (120)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the preparation of a benzo(b)bicyclo[3.3.1]nonene of the general formula I:

I
or a pharmaceutically acceptable acid addition salt or nitrogen oxide there-of, in which R1 and R2 stand for hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, an acyl group or a phenylalkyl group in which the alkyl moiety contains 1 to 6 carbon atoms and in which the phenyl group is unsubstituted or substituted by one or more halogen atoms or lower alkyl or alkoxy groups; R3 represents a free hydroxy group or an etherified or esterified hydroxy group; X and Y are the same or different and represent hydrogen or halogen atoms or alkyl or alkoxy groups of 1 to 6 carbon atoms, nitro, trifluoromethyl or an acyloxy group or R1 and R2 together with the nitrogen atom represent a 5- or 6-membered heterocyclic ring which comprises either:
(a) subjecting a ketone of the general formula II:

II

in which R3, X and Y are as previously defined to reductive amination, by reducing the ketone of formula II in the presence of formamide, N-alkylformamide or N,N-dialkylformamide or an amine of the general formula III:
III

wherein R? and R? have the same meanings as R1 and R2 with the exception of an acyl group; or (b) reducing an imine of the general formula IV:

IV
in which X, Y and R3 are as previously defined and R4 stands for hydrogen, hydroxy, C1-6 alkoxy, C1-6 alkyl or a phenylalkyl group as defined above; or (c) reacting a reactive derivative of a hydroxyl compound of the general formula V:

V

wherein X and Y are as previously defined and R5 represents an etherified or esterified hydroxy group, with an amine of the general formula III as defined above;
(d) when a compound of formula I is required in which R3 is a hydroxy group hydrolysing a corresponding compound of formula I obtained in which R3 is an etherified or esterified hydroxy group;
(e) when a compound of formula I is required in which one or both of R1 and R2 is a hydrogen atom hydrolysing a corresponding compound of formula I
obtained in which one or both of R1 and R2 is an acyl group;
(f) when a compound of formula I is required in which one or both of R1 and R2 is an alkyl group of 1 to 6 carbon atoms, reducing a corresponding compound of formula I obtained in which one or both of R1 and R2 is an alkanoyl group of 1 to 6 carbon atoms;
(g) when a compound of formula I is required in which R3 is an esterified hydroxy group esterifying a corresponding compound of formula I obtained in which R3 is a free hydroxy group;
(h) when a compound of formula I is required in which one or both of R1 and R2 is an alkyl group of 1 to 6 carbon atoms or an alkenyl group of 2 to 6 carbon atoms, alkylating a corresponding compound of formula I obtained in which one or both of R1 and R2 is a hydrogen atom;
(i) when a compound of formula I is required in which one or both of R1 and R2 is an acyl group, acylating a corresponding compound of formula I
in which one or both of R1 and R2 is a hydrogen atom; and where any one of steps (a) to (i) can be followed by the additional step of converting a base of formula I into a corresponding pharmaceutically acceptable acid addition salt or nitrogen oxide.
2. A process according to claim 1(a) in which the ketone of formula I
is reacted with a mixture of formic acid and formamide,N-methylformamide or N,N-dimethylformamide.
3. A process according to claim 1(b) in which the reduction is effected by reaction with sodium in isopropanol.
4. A process according to claim 1(g) in which a compound of formula I
in which R3 is a hydroxy group is acetylated or benzoylated.
5. A process according to claim 1(i) in which the acylation is acetylation or benzoylation.
6. A process according to claim 1(h) in which a compound of formula I
in which one or both of R1 and R2 is a hydrogen atom is methylated by the Eschweiler-Clarke procedure (reaction with formaldehyde and formic acid).
7. A process according to claim 1(f) in which the reduction is effected by reaction with a metal hydride.
8. A process according to claim 7 in which the metal hydride is lithium aluminium hydride.
9. A process according to claim 1(c) in which the reactive derivative is an alkyl or arylsulfonyloxy group or a halogen atom.
10. A process according to claim 1 in which R1 and R2 are the same or different and represent hydrogen atoms, alkyl groups of 1 to 6 carbon atoms, alkenyl groups of 2 to 6 carbon atoms or acyl groups; R3 is a free or esterified hydroxy group; X and Y are the same or different and represent hydrogen or stable halogen atoms, alkyl or alkoxy of 1 to 6 carbon atoms or a nitro group.
11. A process according to claim 1 in which R1 and R2 are the same or different and represent hydrogen atoms, methyl, ethyl, 3-methyl-but-2-enyl, formyl or acetyl groups; R3 is hydroxy, benzoyloxy, acetoxy, p-nitrobenzoyloxy or methoxy; X and Y are the same or different and represent hydrogen, chlorine or bromine atoms or methoxy, nitro or t-butyl groups.
12. A process according to claim 1 in which R1 is formyl, R2 is hydrogen, R3 is benzoyloxy, X is 8-chloro and Y is hydrogen.
13. A process according to claim 1 in which 4-exo-benzoyloxy-8-chloro-11-anti-formamido-benzo(b)bicyclo[3,3,1]nonene is prepared by reacting 4-exo-benzoyloxy-8-chloro-benzo(b)bicyclo[3,3,1]nonen-11-one with a mixture of formic acid and formamide.
14. A process according to claim 1 in which 4-endo-benzoyloxy-8-chloro-ll-anti-formamido-benzo(b)bicyclo[3,3,1]nonene is prepared by reacting 4-endo-benzoyloxy-8-chloro-benzo(b)bicyclo[3,3,1]nonen-11-one with a mixture of formic acid and formamide and separating the resulting mixture of 11-anti and 11-syn-isomers into its individual components by chromatography.
15. A process according to claim 1 in which 4-endo-benzoyloxy-8-chloro-11-syn-formamido-benzo(b)bicyclo[3,3,1]nonene is prepared by reacting 4-endo-benzoyloxy-8-chloro-benzo(b)bicylo[3,3,1]nonen-11-one with a mixture of formic acid and formamide and separating the resulting mixture of 11-anti and 11-syn-isomers into its individual components by chromatography.
16. A process according to claim 1 in which R1 is formyl, R2 and Y are hydrogcn atoms, R3 is acetoxy and X is 8-methoxy.
17. A process according to claim 1 in which 4-exo-acetoxy-8-methoxy-11-anti-formamido-benzo(b)bicyclo[3,3,1]nonene is prepared by reacting 4-exo-acetoxy-8-methoxy-benzo(b)bicyclo[3,3,1]nonen-11-one with a mixture of formic acid and formamide.
18. A process according to claim 1 in which R1 is formyl, R2 and Y are hydrogen atoms, R3 is benzoyloxy and X is 8-bromo.
19. A process according to claim 1 in which 4-exo-benzoyloxy-8-bromo-11-arti-formamido-benzo(b)bicyclo[3,3,1]nonene is prepared by reacting 4-exo-benzoyloxy-8-bromo-benzo(b)bicyclo[3,3,1]nonen-11-one with a mixture of formic acid and formamide.
20. A process according to claim 1 in which 3-endo-benzoyloxy-8-bromo-11-anti-formamido-benzo(b)bicyclo[3,3,1]nonene is prepared by reacting 4-endo-benzoyloxy-8-bromo-benzo(b)bicyclo[3,3,1]nonen-11-one with a mixture of formic acid and formamide.
21. A process according to claim 1 in which R1 is formyl, R2 is a hydrogen atom, R3 is benzoyloxy, X is 8-chloro and Y is 9-chloro.
220 A process according to claim 1 in which 4-exo-benzoyloxy-8,9-dichloro-11-anti-formamido-benzo(b)bicyclo[3,3,1]nonene is prepared by reacting 4-exo-benzoyloxy-8,9-dichloro-benzo(b)bicyclo[3,3,1]nonen-11-one with a mixture of formic acid and formamide.
23. A process according to claim 1 in which R1 is formyl, R2 and Y are hydrogen atoms, R3 is p-nitrobenzoyloxy and X is 9-chloro.
24. A process according to claim 1 in which 4-endo-p-nitrobenzoyloxy-9-chloro-11-anti-formamido-benzo(b)bicyclo[3,3,1]nonene is prepared by reacting 4-endo-p-nitrobenzoyloxy-9-chloro-benzo(b)bicyclo[3,3,1]nonen-11-one with a mixture of formic acid and formamide and separating the resulting mixture of 11-anti-and 11-syn-isomers into its individual components by chromatography.
25. A process according to claim l in which 4-endo-p-nitrobenzoyloxy-9-chloro-11-syn-formamido-benzo(b)bicyclo[3,3,1]nonene is prepared by reacting 4-endo-p-nitrobenzoyloxy-9-chloro-benzo(b)bicyclo[3,3,1]nonen-11-one with a mixture of formic acid and formamide and separating the resulting mixture of 11-anti-and 11-syn-isomers into its individual components by chromatography.
26. A process according to claim 1 in which R1 is formyl, R2, X and Y
are hydrogen atoms and R3 is acetoxy.
27. A process according to claim 1 in which 4-exo-acetoxy-11-anti-formamido-benzo(b)bicyclo[3,3,1]nonene is prepared by reacting 4-exo-acetoxy-benzo(b)bicyclo[3,3,1]nonen-11-one with a mixture of formic acid and formamide and separating the resulting mixture of 11-anti-and 11-syn-isomers into its individual components by chromatography.
28. A process according to claim 1 in which 4-exo-acetoxy-11-syn-formamido-benzo(b)bicyclo[3,3,1]nonene is prepared by reacting 4-exo-acetoxy-benzo(b)bicyclo[3,3,1]nonen-11-one with a mixture of formic acid and formamide and separating the resulting mixture of 11-anti-and 11-syn-isomers into its individual components by chromatography.
29. A process according to claim 1 in which R1, R2 and Y are hydrogen atoms, R3 is hydroxy and X is 8-chloro.
30. A process according to claim 1 in which 4-exo-hydroxy-8-chloro-11-anti-amino-benzo(b)bicyclo[3,3,1]nonene and its hydrochloride are prepared by hydrolysing 4-exo-benzoyloxy-8-chloro-11-anti-formamido-benzo(b)bicyclo[3,3,1]-nonene and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.
31. A process according to claim 1 in which R1, R2 and Y are hydrogen atoms, R3 is hydroxy and X is 8-methoxy.
32. A process according to claim 1 in which 4-exo-hydroxy-8-methoxy-ll-anti-amino-benzo(b)bicyclo[3,3,1]nonene and its hydrochloride are prepared by reducing 4-exo-hydroxy-8-methoxy-benzo(b)bicyclo[3,3,1]nonen-11-oxime and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.
33. A process according to claim 32 in which the reduction is effected by reaction with sodium in isopropanol.
34. A process according to claim 1 in which 4-exo-hydroxy-8-methoxy-11-anti-amino-benzo(b)bicyclo[3,3,1]nonene and its hydrochloride are prepared by hydrolysing 4-exo-benzoyloxy-8-methoxy-11-anti-formamido-benzo(b)bicyclo [3,3,1]nonene and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.
35. A process according to claim 1 in which R1 and R2 are hydrogen atoms, R3 is a hydroxy group, X is 8-chloro and Y is 9-chloro.
36. A process according to claim 1 in which 4-exo-hydroxy-8,9-dichloro-11-anti-amino-benzo(b)bicyclo[3,3,1]nonene and its hydrochloride are prepared by reducing 4-exo-hydroxy-8,9-dichlorobenzo(b)bicyclo[3,3,1]nonen-11-oxime and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.
37. A process according to claim 36 in which the reduction is effected by reaction with sodium in isopropanol.
38. A process according to claim 1 in which 4-exo-hydroxy-8,9-dichloro-11-anti-amino-benzo(b)bicyclo[3,3,1]nonene and its hydrochloride are prepared by hydrolysing 4-exo-benzoyloxy-8,9-dichloro-11-anti-formamido-benzo(b) bicyclo[3,3,1]nonene and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.
39. A process according to claim 1 in which R1, R2, X and Y are hydrogen atoms and R3 is a hydroxy group.
40. A process according to claim 1 in which 4-exo-hydroxy -11-anti-amino-benzo(b)bicyclo[3,3,1]nonene and its hydrochloride are prepared by reducing 4-exo-hydroxy-benzo(b)bicyclo[3,3,1]nonen-11-oxime and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.
41. A process according to claim 40 in which the reduction is effected by reaction with sodium in isopropanol.
42. A process according to claim 1 in which 4-exo-hydroxy-11-anti-amino-benzo(b)bicyclo[3,3,1]nonene and its hydrochloride are prepared by hydrolysing 4-exo-benzoyloxy-11-anti-formamido-benzo(b)bicyclo[3,3,1]nonene and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.
43. A process according to claim 1 in which R1 is methyl, R2 and Y are hydrogen atoms, R3 is hydroxy and X is 8-chloro.
44. A process according to claim 1 in which 4-exo-hydroxy-8-chloro-11-anti-methylamino-benzo(b)bicyclo[3,3,1]nonene and its hydrochloride are prepared by reducing and hydrolysing 4-exo-benzoyloxy-8-chloro-11-anti-formamido-benzo(b) bicyclo[3,3,1]nonene and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.

3?
45. A process according to claim 44 in which the reduction and hydrolysis are effected by reaction with lithium aluminium hydride followed by treatment with water.
46. A process according to claim 1 in which 4-endo-hydroxy-8-chloro-11-anti-methylamino-benzo(b)bicyclo[3,3,1]nonene and its hydrochloride are prepared by reducing and hydrolysing either 4-endo-acetoxy or 4-endo-benzoyloxy-8-chloro-11-anti-formamido-benzo(b)bicyclo[3,3,1]nonene and separating the resulting mixture of 11-anti-and 11-syn-isomers into its individual components by chromatography and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.
47. A process according to claim 46 in which the reduction and hydrolysis are effected by reaction with lithium aluminium hydride followed by treatment with water.
48. A process according to claim 1 in which R1 is methyl, R2 and Y are hydrogen atoms, R3 is hydroxy and X is 8-bromo.
49. A process according to claim 1 in which 4-exo-hydroxy-8-bromo-11-anti-methylamino-benzo(b)bicyclo[3,3,1]nonene and its hydrochloride are prepared by reacting 4-exo-benzoyloxy-8-bromo-benzo(b)bicyclo[3,3,1]nonen-11-one with a mixture of formic acid and N-methyl-formamide and hydrolysing the compound so obtained and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.
50. A process according to claim 1 in which R1 is methyl, R2 and Y are hydrogen atoms, R3 is acetoxy and X is 8-chloro.
51. A process according to claim 1 in which 4-exo-acetoxy-8-chloro-11-anti-methylamino-benzo(b)bicyclo[3,3,1]nonene and its hydrochloride are prepared by acetylating 4-exo-hydroxy-8-chloro-11-anti-methylamino-benzo(b)-bicyclo[3,3,1]nonene and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.
52. A process according to claim 1 in which R1, R2 and Y are hydrogen atoms, R3 is acetoxy and X is 8-chloro.
53. A process according to claim 1 in which 4-exo-acetoxy-8-chloro-11 anti-amino-benzo(b)bicyclo[3,3,1]nonene and its hydrochloride are prepared by acetylating 4-exo-hydroxy-8-chloro-11-anti-amino-benzo(b)bicyclo[3,3,1]nonene and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.
54. A process according to claim 1 in which 4-endo-acetoxy-8-chloro-11-anti-amino-benzo(b)bicyclo[3,3,1]nonene and its hydrochloride are prepared by acetylating 4-endo-hydroxy-8-chloro-11-anti-amino-benzo(b)bicyclo[3,3,1]nonene and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.
55. A process according to claim 1 in which R1 is methyl, R2 is a hydrogen atom, R3 is acetoxy, X is 8-chloro and Y is 9-chloro.
56. A process according to claim 1 in which 4-exo-acetoxy-8,9-dichloro-11-anti-methylamino-benzo(b)bicyclo[3,3,1]nonene and its hydrochloride are prepared by acetylating 4-exo-hydroxy-8,9-dichloro-11-anti-methylamino-benzo(b)bicyclo[3,3,1]nonene and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.
57. A process according to claim 1 in which R1, R2 and Y are hydrogen atoms, R3 is benzoyloxy and X is 8-chloro.
58. A process according to claim 1 in which 4-exo-benzoyloxy-8-chloro-11-anti-amino-benzo(b)bicyclo[3,3,1]nonene and its hydrochloride are prepared by benzoylating 4-exo-hydroxy-8-chloro-11-anti-amino-benzo(b)bicyclo[3,3,1]
nonene and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.
59. A process according to claim 1 in which R1 and R2 are methyl groups, R3 is hydroxy, X is 8-chloro and Y is 9-chloro.
60. A process according to claim 1 in which 4-exo-hydroxy-8,9-dichloro-11-anti-dimethylamino-benzo(b)bicyclo[3,3,1]nonene and its hydrochloride are prepared by methylating 4-exo-hydroxy-8,9-dichloro-11-anti-amino-benzo (b)-bicyclo[3,3,1]nonene and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.
61. A process according to claim 1 in which 4-exo-hydroxy-8,9-dichloro-11-anti-dimethylamino-benzo(b)bicyclo[3,3,1]nonene and its hydrochloride are prepared by reacting 4-exo-benzoyloxy-8,9-dichloro-benzo(b)bicyclo[3,3,1]nonen-11-one with a mixture of formic acid and dimethylformamide and hydrolysing the compound so obtained and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.
62. A process according to claim 1 in which R1 and R2 are methyl groups, R3 is acetoxy, X is 8-chloro and Y is 9-chloro.
63. A process according to claim 1 in which 4-exo-acetoxy-8,9-dichloro-11-anti-dimethylamine-benzo(b)bicyclo[3,3,1]nonene and its hydrochloride are prepared by acetylating 4-exo-hydroxy-8,9-dichloro-11-anti-dimethylamino-benzo(b)bicyclo[3,3,1]nonene and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.
64. A process according to claim 1 in which R1 is acetyl, R2, X and Y
are hydrogen atoms and R3 is acetoxy.
65. A process according to claim 1 in which 4-exo-acetoxy-11-anti-acetamido-benzo(b)bicyclo[3,3,1]nonene is prepared by acetylating 4-exo-hydroxy-11-anti-amino-benzo(b)bicyclo[3,3,1]nonene.
66. A process according to claim 1 in which R1 is ethyl, R2, X and Y
are hydrogen atoms and R3 is acetoxy.
67. A process according to claim 1 in which 4-exo-hydroxy-11-anti-ethylamino-benzo(b)bicyclo[3,3,1]nonene and its hydrochloride are prepared by reducing 4-exo-acetoxy-11-anti-acetamido-benzo(b)bicyclo[3,3,1]nonene and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.
68. A process according to claim 1 in which R1 is methyl, R2 is 3-methyl-but-2-enyl, R3 is hydroxy and X and Y are hydrogen atoms.
69. A process according to claim 1 in which 4-exo-hydroxy-11-anti-N-methyl-N-(3-methyl-but-2-enyl)amino-benzo(b)bicyclo[3,3,1]nonene and its hydro-chloride are prepared by 3-methyl-but-2-enylating 4-exo-hydroxy-11-anti-methylamino-benzo(b)bicyclo[3,3,1]nonene and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.
70. A process according to claim 1 in which R1 is formyl, R2 and Y are hydrogen atoms, R3 is exo-p-nitrobenzoyloxy and X is 9-chloro.
71. A process according to claim 1 in which 4-exo-p-nitro-benzoyloxy-9-chloro-11-anti-formamido-benzo(b)bicyclo[3,3,1]nonene and its hydrochloride are prepared by reacting 4-exo-p-nitrobenzoyloxy-9-chloro-benzo(b)bicyclo[3,3,1]-nonen-11-one with a mixture of formic acid and formamide and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.
72. A procsss according to claim 1 in which Rl is formyl, R2 is a hydrogen atom, R3 is p-nitrobenzoyloxy, X is 8-nitro and Y is 9-chloro.
73. A process according to claim 1 in which 4-exo-p-nitrobenzoyloxy-8-nitro-9-chloro-11-anti-formamido-benzo(b)bicyclo[3,3,1]nonene and its hydro-chloride are prepared by reacting 4-exo-p-nitrobenzoyloxy-8-nitro-9-chloro-benzo(b)bicyclo[3,3,1]nonen-11-one with a mixture of formic acid and formamide, and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.
74. A process according to claim 1 in which R1 is formyl, R2 is a hydrogen atom, R3 is p-nitrobenzoyloxy, X is 10-nitro and Y is 9-chloro.
75. A process according to claim 1 in which 4-exo-p-nitrobenzoyloxy-9-chloro-10-nitro-11-anti-formamido-benzo(b)bicyclo[3,3,1]nonene and its hydrochloride are prepared by reacting 4-exo-p-nitrobenzoyloxy-9-chloro-10-nitro-benzo(b)-bicyclo[3,3,1]nonen-11-one with a mixture of formic acid and formamide, and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.
76. A process according to claim 1 in which 4-endo-p-nitrobenzoyloxy-8-nitro-9-chloro-11-anti-formamido-benzo(b)bicyclo[3,3,1]nonene and its hydro-chloride are prepared by reacting 4-endo-p-nitrobenzoyloxy-8-nitro-9-chloro-benzo(b)bicyclo[3,3,1]nonen-11-one with a mixture of formic acid and formamide, and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.
77. A process according to claim 1 in which R1 is formy, R2 is a hydrogen atom, R3 is hydroxy, X is 9-nitro and Y is 8-chloro.
78. A process according to claim 1 in which 4-exo-hydroxy-8-chloro-9-nitro-11-anti-formamido-benzo(b)bicyclo[3,3,1]nonene and its hydrochloride are prepared by reacting 4-exo-hydroxy-8 -chloro-9-nitro-benzo(b)bicyclo[3,3,1]-nonen-11-one with a mixture of formic acid and formamide, and when the hydro-chloride is required reacting the base so obtained with hydrogen chloride.
79. A process according to claim 1 in which R1 and R2 are methyl groups, R3 is methoxy, X is 8-chloro and Y is a hydrogen atom.
80. A process according to claim 1 in which 4-exo-methoxy-8-chloro-11-anti-dimethylamino-benzo(b)bicyclo[3,3,1]nonene is prepared by reacting 4-exo-methoxy-8-chloro-benzo(b)bicyclo[3,3,1]nonen-11-one with a mixture of formic acid and N,N-dimethylformamide.
81. A process according to claim 1 in which R1 and R2 are methyl groups, R3 is hydroxy, X is 8-t-butyl and Y is a hydrogen atom.
82. A process according to claim 1 in which 4-exo-hydroxy-8-t-butyl-11-anti-dimethylamino-benzo(b)bicyclo[3,3,1]nonene is prepared by reacting 4-exo-hydroxy-8-t-butyl-benzo(b)bicyclo[3,3,1]nonen-11-one with a mixture of formic acid and N,N-dimethylformamide.
83. A compound of the general formula I given in claim 1 or a pharmaceutically acceptable acid addition salt or nitrogen oxide thereof whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
84. A compound of the general formula I given in claim 1 or a pharmaceutically acceptable acid addition salt or nitrogen oxide thereof wherein R1, R2, R3, X and Y are as defined in claim 10 whenever prepared by the process of claim 10 or by an obvious chemical equivalent thereof.
85. A compound of the general formula I given in claim 1 or a pharmaceutically acceptable acid addition salt or nitrogen oxide thereof, wherein Rl, R2, R3 X and Y are as defined in claim 11 whenever prepared by the process of claim 11 or by an obvious chemical equivalent thereof.
86. 4-exo-Benzoyloxy-8-chloro-11-anti-formamido-benzo(b)bicyclo[3,3,1]-nonene whenever prepared by the process of claim 13 or by an obvious chemical equivalent thereof.
87. 4-endo-Benzoyloxy-8-chloro-11-anti-formamido-benzo(b)bicyclo[3,3,1]-nonene whenever prepared by the process of claim 14 or by an obvious chemical equivalent thereof.
88. 4-endo-Benzoyloxy-8-chloro-11-syn-formamido-benzo(b)bicyclo[3,3,1]-nonene whenever prepared by the process of claim 15 or by an obvious chemical equivalent thereof.
89. 4-exo-Acetoxy-8-methoxy-11-anti-formamido-benzo(b)bicyclo[3,3,1]nonene whenever prepared by the process of claim 17 or by an obvious chemical equivalent thereof.
90. 4-exo-Benzoyloxy-8-bromo-11-anti-formamido-benzo(b)bicyclo[3,3,1]nonene whenever prepared by the process of claim 19 or by an obvious chemical equivalent thereof.
91. 4-endo-Benzoyloxy-8-bromo-11-anti-formamido-benzo(b)bicyclo[3,3,1]-nonene whenever prepared by the process of claim 20 or by an obvious chemical equivalent thereof.
92. 4-exo-Benzoyloxy-8,9-dichloro-11-anti-formamido-benzo(b)bicyclo[3,3,1]-nonene whenever prepared by the process of claim 22 or by an obvious chemical equivalent thereof.
93. 4-endo-p-Nitrobenzoyloxy-9-chloro-11-anti-formamido-benzo(b)bicyclo-[3,3,1]nonene whenever prepared by the process of claim 24 or by an obvious chemical equivalent thereof.
94. 4-endo-p-Nitrobenzoyloxy-9-chloro-11-syn-formamido-benzo(b)bicyclo-[3,3,1]nonene whenever prepared by the process of claim 25 or by an obvious chemical equivalent thereof.
95. 4-exo-Acetoxy-11-anti-formamido-benzo(b)bicyclo[3,3,1]nonene whenever prepared by the process of claim 27 or by an obvious chemical equivalent thereof.
96. 4-exo-Acetoxy-11-syn-formamido-benzo(b)bicyclo[3,3,1]nonene whenever prepared by the process of claim 28 or by an obvious chemical equivalent thereof.
97. 4-exo-Hydroxy-8-chloro-11-anti-amino-benzo(b)bicyclo[3,3,1]nonene and its hydrochloride whenever prepared by the process of claim 30 or by an obvious chemical equivalent thereof.
98. 4-exo-Hydroxy-8-methoxy-11-anti-amino-benzo(b)bicyclo[3,3,1]nonene and its hydrochloride whenever prepared by the process of claim 32, 33 or 34 or by an obvious chemical equivalent thereof.
99. 4-exo-Hydroxy-8,9-dichloro-11-anti-amino-benzo(b)bicyclo[3,3,1]-nonene and its hydrochloride whenever prepared by the process of claim 36, 37 or 38 or by an obvious chemical equivalent thereof.
100. 4-exo-Hydroxy-11-anti-amino-benzo(b)bicyclo[3,3,1]nonene and its hydrochloride whenever prepared by the process of claim 40, 41 or 42 or by an obvious chemical equivalent thereof.
101. 4-exo-Hydroxy-8-chloro-11-anti-methylamino-benzo(b)bicyclo[3,3,1]-nonene and its hydrochloride whenever prepared by the process of claim 44 or 45 or by an obvious chemical equivalent thereof.
102. 4-endo-Hydroxy-8-chloro-11-anti-methylamino-benzo(b)bicyclo[3,3,1]-nonene and its hydrochloride whenever prepared by the process of claim 46 or 47 or by an obvious chemical equivalent thereof.
103. 4-exo-Hydroxy-8-bromo-11-anti-methylamino-benzo(b)bicyclo[3,3,1]-nonene and its hydrochloride whenever prepared by the process of claim 49 or by an obvious chemical equivalent thereof.
104. 4-exo-Acetoxy-8-chloro-11-anti-methylamino-benzo(b)bicyclo [3,3,1]-nonene and its hydrochloride whenever prepared by the process of claim 51 or by an obvious chemical equivalent thereof.
105. 4-exo-Acetoxy-8-chloro-11-anti-amino-benzo(b)bicyclo[3,3,1]nonene and its hydrochloride whenever prepared by the process of claim 53 or by an obvious chemical equivalent thereof.
106. 4-endo-Acetoxy-8-chloro-11-anti-amino-benzo (b)bicyclo[3, 3,1]nonene and its hydrochloride whenever prepared by the process of claim 54 or by an obvious chemical equivalent thereof.
107. 4-exo-Acetoxy-8,9-dichloro-11-anti-methylamino-benzo(b)bicyclo[3,3,1]-nonene and its hydrochloride whenever prepared by the process of claim 56 or by an obvious chemical equivalent thereof.
108. 4-exo-Benzoyloxy-8-chloro-11-anti-aminobenzo(b)bicyclo[3,3,1]nonene and its hydrochloride whenever prepared by the process of claim 58 or by an obvious chemical equivalent thereof.
109. 4-exo-Hydroxy-8,9-dichloro-11-anti-dimethylamino-benzo(b)bicyclo-[3,3,1]nonene and its hydrochloride whenever prepared by the process of claim 60 or by an obvious chemical equivalent thereof.
110. 4-exo-Acetoxy-8,9-dichloro-11-anti-dimethylamine-benzo(b)bicyclo-[3,3,1]nonene and its hydrochloride whenever prepared by the process of claim 63 or by an obvious chemical equivalent thereof.
111. 4-exo-Acetoxy-11-anti-acetamido-benzo(b)bicyclo[3,3,1]nonene whenever prepared by the process of claim 65 or by an obvious chemical equivalent thereof.
112. 4-exo-Hydroxy-11-anti-ethylamino-benzo(b)bicyclo[3,3,1]nonene and its hydrochloride whenever prepared by the process of claim 67 or by an obvious chemical equivalent thereof.
113. 4-exo-Hydroxy-11-anti-N-methyl-N-(3-methyl-but-2-enyl)amino-benzo(b)-bicyclo[3,3,1]nonene and its hydrochloride whenever prepared by the process of claim 69 or by an obvious chemical equivalent thereof.
114. 4-exo-p-Nitrobenzoyloxy-9-chloro-11-anti-formamido-benzo(b)bicyclo-[3,3,1]nonene and its hydrochloride whenever prepared by the process of claim 71 or by an obvious chemical equivalent thereof.
115. 4-exo-p-Nitrobenzoyloxy-8-nitro-9-chloro-11-anti-formamido-benzo(b)-bicyclo[3,3,1]nonene and its hydrochloride whenver prepared by the process of claim 73 or by an obvious chemical equivalent thereof.
116. 4-exo-p-Nitrobenzoyloxy-9-chloro-10-nitro-11-anti-formamido-benzo(b)-bicyclo[3,3,1]nonene and its hydrochloride whenever prepared by the process of claim 75 or by an obvious chemical equivalent thereof.
117. 4-endo-p-Nitrobenzoyloxy-8-nitro-9-chloro-11-anti-formamido-benzo(b)-bicyclo[3,3,1]nonene and its hydrochloride whenever prepared by the process of claim 76 or by an obvious chemical equivalent thereof.
118. 4-exo-Hydroxy-8-chloro-9-nitro-11-anti-formamido-benzo(b)bicyclo-[3,3,1]nonene and its hydrochloride whenever prepared by the process of claim 78 or by an obvious chemical equivalent thereof.
119. 4-exo-Methoxy-8-chloro-11-anti-dimethylamino-benzo(b)bicyclo[3,3,1]-nonene whenever prepared by the process of claim 80 or by an obvious chemical equivalent thereof.
120. 4-exo-Hydroxy-8-t-butyl-11-anti-dimethylamino-benzo(b)bicyclo[3,3,1]-nonene whenever prepared by the process of claim 82 or by an obvious chemical equivalent thereof.
CA251,293A 1975-04-29 1976-04-28 Benzobicyclononene derivatives Expired CA1077954A (en)

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JP (1) JPS51131868A (en)
AU (1) AU501107B2 (en)
BE (1) BE841244A (en)
CA (1) CA1077954A (en)
CH (2) CH628612A5 (en)
DE (1) DE2618721C2 (en)
DK (1) DK187076A (en)
FI (1) FI64573C (en)
FR (1) FR2309218A1 (en)
GB (1) GB1549172A (en)
HU (1) HU176463B (en)
IE (1) IE44118B1 (en)
LU (1) LU74856A1 (en)
NL (1) NL7506408A (en)
SE (1) SE433744B (en)
ZA (1) ZA762359B (en)

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GB1570613A (en) * 1976-10-27 1980-07-02 Akzo Nv Biologically active tricyclic compounds and pharmaceutical compositions containing same
GB8606061D0 (en) * 1986-03-12 1986-04-16 Akzo Nv Tricyclic amino compounds

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JPS51131868A (en) 1976-11-16
FI761189A (en) 1976-10-30
FR2309218B1 (en) 1978-08-25
CH632985A5 (en) 1982-11-15
SE433744B (en) 1984-06-12
AU1328976A (en) 1977-10-27
BE841244A (en) 1976-10-28
JPS6154776B2 (en) 1986-11-25
AU501107B2 (en) 1979-06-14
GB1549172A (en) 1979-08-01
NL7506408A (en) 1976-11-02
LU74856A1 (en) 1977-01-12
ZA762359B (en) 1977-04-27
DE2618721C2 (en) 1986-06-05
FR2309218A1 (en) 1976-11-26
DE2618721A1 (en) 1976-11-11
IE44118B1 (en) 1981-08-26
DK187076A (en) 1976-10-30
FI64573C (en) 1983-12-12
HU176463B (en) 1981-03-28
CH628612A5 (en) 1982-03-15
SE7604861L (en) 1976-10-30
IE44118L (en) 1976-10-29
FI64573B (en) 1983-08-31

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