GB2367554A - Pharmacologically active amines - Google Patents

Pharmacologically active amines Download PDF

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Publication number
GB2367554A
GB2367554A GB0024318A GB0024318A GB2367554A GB 2367554 A GB2367554 A GB 2367554A GB 0024318 A GB0024318 A GB 0024318A GB 0024318 A GB0024318 A GB 0024318A GB 2367554 A GB2367554 A GB 2367554A
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Prior art keywords
bicyclo
methyl
hept
naphthyl
oct
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GB0024318A
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GB0024318D0 (en
Inventor
Martine Keenen
Vincent Rocco
Jean Takeuchi
David Edward Tupper
Vincent Vivien
Kumiko Takeuchi
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Eli Lilly and Co
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Eli Lilly and Co
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Priority to GB0024318A priority Critical patent/GB2367554A/en
Publication of GB0024318D0 publication Critical patent/GB0024318D0/en
Priority to PCT/US2001/027725 priority patent/WO2002028815A1/en
Priority to US10/363,781 priority patent/US20040030131A1/en
Priority to EP01972947A priority patent/EP1326824A1/en
Priority to CA002419777A priority patent/CA2419777A1/en
Priority to JP2002532402A priority patent/JP2004510754A/en
Priority to AU2001292578A priority patent/AU2001292578A1/en
Publication of GB2367554A publication Critical patent/GB2367554A/en
Withdrawn legal-status Critical Current

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Abstract

A compound of the formula <EMI ID=1.1 HE=40 WI=80 LX=725 LY=552 TI=CF> <PC>in which R<SP>1</SP> and R<SP>2</SP> are each hydrogen or C<SB>1-4</SB> alkyl, or R<SP>1</SP> and R<SP>2</SP> together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholino group, said group being optionally substituted with 1 to 3 substituents selected from C<SB>1-4</SB> alkyl, hydroxymethyl, C<SB>1-4</SB> alkoxymethyl and amido,<BR> R<SP>3</SP> is a naphthyl, indolyl, benzothienyl, benzofuranyl, benzothiazolyl, quinolinyl or isoquinolinyl group, said group being optionally substituted, and n is 1 or 2; and m is 0 or 1, provided that when m is 1 then n is 1;<BR> or a salt or ester thereof,<BR> has pharmacological effects on the central nervous system.

Description

PHARMACEUTICAL COMPOUNDS
This invention relates to novel compounds having pharmaceutical properties.
Certain aminoalkyl bicycloheptanes having a pharmacological effect on the central nervous system, are disclosed in British Patent 1 586 249. Also, British Patents 1 444 717 and 1 549 174 describe aminoalkyl bicyclooctyl derivatives with similar properties.
The compounds of the invention are of the following formula:
in which Rl and R2 are each hydrogen or Cl-4 alkyl, or Rl and R2 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholino group, said group being optionally substituted with 1 to 3 substituents selected from Cl-4 alkyl, hydroxymethyl, Cl-4 alkoxymethyl and amido,
R3 is a naphthyl, indolyl, benzothienyl, benzofuranyl, benzothiazolyl, quinolinyl or isoquinolinyl group, said group being optionally substituted, and n is 1 or 2 and m is 0 or 1, provided that when m is 1 then n is 1; or a salt or ester thereof.
The compounds of the invention and their pharmaceutically acceptable salts and esters are indicated for use in the treatment of disorders of the central nervous system.
In the above formula (I), RI and R2 are preferably hydrogen or Cl-4 alkyl. When R1 and R2 combine to form one of the cyclic rings mentioned above, they can be substituted with Cl-4 alkyl, hydroxymethyl, Cl-4 alkoxymethyl or amido. An amido group is preferably a C2-5 acylamido substituent of the formula Cl-4 alkyl CONH-, and is most preferebly acetamido.
A Cl-4 alkyl group can be methyl, ethyl, or propyl, and can be branched or unbranched and includes isopropyl and tert. butyl. Preferably RI and R2 are each hydrogen, methyl or ethyl, and especially hydrogen or methyl. The
- NR1R2 group is preferably-N (CH3) 2 and most preferably - NH (CH3). Compounds of formula (I) in which n is 1 and m is 0, are 2.2. 1 bicycloheptyl derivatives of the structure:
Compounds of formula (I) in which n is 1 and m is 1, are 3.2. 1 bicyclooctyl derivatives of the structure
Compounds of formula (I) in which n is 2 and m is 0 are 2.2. 2 bicycloocyl derivatives of the structure:
The R3 substituent is attached to the bicyclo ring at certain positions on the substituent, and examples of R3
groups are a-naphthyl, p-naphthyl, 2-, 3-, 4-, 5-, 6-or 7-indolyl, 2-, 3-, 4-, 5-, 6-or 7-benzothienyl, 2-, 3-, 4-, 5-, 6-or 7-benzofuranyl, 2-, 3-, 4-, 5-, 6-or 7benzothiazolyl, 2-, 3-, 4-, 5-, 6-or 7-quinolinyl or 3-, 4-, 5-, 6-or 7-isoquinolinyl. Preferred R3 substituents are, 2-, 3-, 4-, 5-, 6-or 7-benzothienyl, and especially 4-, 5-or 7-benzothienyl.
The R3 group can also be substituted, substitution being in one or both rings, with one or more, preferably 1 to 3, substituents. Preferred substituents include Cl-4 alkyl, Cl-4 alkoxy, carboxy, nitro, hydroxy, cyano, halo, trifluoromethyl, trifluromethoxy, optionally substituted benzyl, optionally substituted benzyloxy
- NR'R'',-CONR'R'',-SO2NR'R''and-SO2R', where R'and R''are each hydrogen or Cl-4 alkyl. A halo substituant is preferably chloro, bromo or fluoro. A benzyl or benzyloxy group is optionally substituted on the phenyl ring with one of the substituents listed above.
Especially preferred substituents are Cl-4 alkyl, halo and cyano.
As indicated above, it is possible to prepare salts of the compound of the invention and such salts are included in the invention. Such salts are preferably
the pharmaceutically acceptable, non-toxic salts. Of special interest are acid addition salts, in particular those with suitable acids, such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example, maleic, fumaric, tartaric or citric acid.
In addition to the pharmaceutically acceptable salts, other salts are included in the invention. They may serve as intermediates in the purification of compounds or in the preparation of other, for example pharmaceutically acceptable, acid addition salts, or are useful for identification, characterisation or purification.
It will be appreciated that when a substituent on an R3 group is acidic such as, for example, a carboxy group, the opportunity exists for esters. These can be aliphatic or aromatic, being preferably alkyl esters derived from Cl-4 alkanols, especially methyl and ethyl esters. An example of an ester substituent is-COOR' where RI is CI-4 alkyl.
The bicyclo compounds of the 2. 2. 1 and 3. 2. 1 systems contain asymmetric carbon atoms as indicated by asterisks in the following structures:
Thus R and S enantiomeric forms of these compounds exist. The compounds can be prepared as racemic mixtures and can conveniently be used a such, but individual isomers can be isolated by conventional techniques, or are preferably prepared by chiroselective methods. Both racemic mixtures and individual isomers are included in the present invention.
A preferred group of compounds of formula (I) is one in which Rl and R2 are each hydrogen or Cl-4 alkyl, and R3 is optionally substituted benzothienyl, said optionally substituted benzothienyl preferably being attached at the 4-or 7-position.
A further preferred group of compounds of the invention can be represented as follows:
in which Ri and R2 are each hydrogen or Cl-4 alkyl, R6 and R7 are each Cl-4 alkyl, Cl-4 alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl,-NR'R'',-CONR'R'', - S02NR'R''or-SO2R'where R'and R''are each hydrogen or Cl-4 alkyl, and p and q are each 0, 1 or 2 ; or a salt thereof.
The bicyclo moiety can be attached at the 4-, 5-, 6-or 7-position, preferably the 4-or 7-position, and most preferably at the 4-position.
Examples of compounds of the invention, which can be as free base or in the form of a pharmaceutically acceptable salt, and in isomeric or racemic forms, are as follows:
dimethyl- [3- (4-methoxybenzo [b] thiophen-2yl) bicyclo [2. 2. 1] hept-2-en-2-yl] methanamine N, N-dimethyl [3- (2-naphthyl) bicyclo [2. 2. 1] hept-2-en-2yl] methanamine [3- (l-benzothien-2-yl) bicyclo [2. 2. 1] hept-2-en-2-yl]-N, Ndimethylmethanamine [3- (3-bromo-l-benzothien-2-yl) bicyclo [2. 2. 1] hept-2-en-2yl]-N, N-dimethylmethanamine [3- (6-methoxy-2-naphthyl) bicyclo [2. 2. 1] hept-2-en-2-yl] N, N-dimethylmethanamine [3- [l, l'-biphenyl]-4-ylbicyclo [2. 2. 1] hept-2-en-2-yl] N, N-dimethylmethanamine [3- (l, 3-benzodioxol-5-yl) bicyclo [2. 2. 1] hept-2-en-2-yl]- N, N-dimethylmethanamine 6- (3-[ (dimethylamino) methyl]bicyclo[2. 2. 1] hept-2-en-2- yl}-2-naphthol [3-(6-bromo-2-naphthyl)bicyclo[2. 2. 1] hept-2-en-2-yl] N, N-dimethylmethanamine
[3- (1-benzofuran-2-yl) bicyclo[2. 2. 1] hept-2-en-2-yl]-N, Ndimethylmethanamine [3- (6-fluoro-2-naphthyl) bicyclo [2. 2. 1] hept-2-en-2-yl] N, N-dimethylmethanamine N, N-dimethyl-3- (3-pyridinyl) bicyclo [2. 2. 1] hept-2-en-2yl] methanamine (1-benzothien-5-yl) bicyclo [2. 2. 1] hept-2-en-2-yl]-N, Ndimethylmethanamine [3- (1-benzothien-3-yl) bicyclo [2. 2. 1] hept-2-en-2-yl]-N, Ndimethylmethanamine N, N-dimethyl [3- (3-quinolinyl) bicyclo [2. 2. 1] hept-2-en-2yl] methanamine N, N-dimethyl [3- (5-methyl-l-benzothien-2yl) bicyclo [2. 2. 1] hept-2-en-2-yl] methanamine N, N-dimethyl [3- (6-methyl-2-naphthyl) bicyclo [2. 2. 1] hept2-en-2-yl] methanamine [3- (l-benzothien-6-yl) bicyclo [2. 2. 1] hept-2-en-2-yl]-N, N
dimethylmethanamine [3- (6-chloro-l, 3-benzothiazol-2-yl) bicyclo [2. 2. 1] hept-2en-2-yl]-N, N-dimethylmethanamine N, N-dimethyl {3- [6- (methylsulfonyl)-2naphthyl] bicyclo [2. 2. 1] hept-2-en-2-yl} methanamine [3- (6-methoxy-l-benzothien-2-yl) bicyclo [2. 2. 1] hept-2-en2-yl]-N, N-dimethylmethanamine [3- (5-methoxy-l-benzothien-2-yl) bicyclo [2. 2. 1] hept-2-en 2-yl]-N, N-dimethylmethanamine [3-(8-methoxy-2-naphthyl)bicyclo[2. 2. 1] hept-2-en-2-yl] N, N-dimethylmethanamine N, N-dimethyl[3-(2-quinolinyl)bicyclo[2. 2. 1] hept-2-en-2- yl] methanamine
[3- (4-isoquinolinyl) bicyclo [2. 2. 1] hept-2-en-2-yl]-N, Ndimethylmethanamine N, N-dimethyl [3- (6-quinolinyl) bicyclo [2. 2. 1] hept-2-en-2yl] methanamine
N, N-dimethyl [3- (2-quinolinyl) bicyclo [2. 2. 1] hept-2-en-2yl] methanamine [3- (4-isoquinolinyl) bicyclo [2. 2. 1] hept-2-en-2-yl]-N, Ndimethylmethanamine N, N-dimethyl [3- (8-quinolinyl) bicyclo [2. 2. 1] hept-2-en-2yl] methanamine N, N-dimethyl [3- (5-quinolinyl) bicyclo [2. 2. 1] hept-2-en-2yl] methanamine [3- (6-fluoro-l-benzothien-3-yl) bicyclo [2. 2. 1] hept-2-en2-yl]-N, N-dimethylmethanamine N, N-dimethyl [3- (2-methyl-6quinolinyl) bicyclo [2. 2. 1] hept-2-en-2-yl] methanamine N, N-dimethyl [3- (4-methyl-2quinolinyl) bicyclo [2. 2. 1] hept-2-en-2-yl] methanamine N, N-dimethyl[3- (2-methyl-l, 3-benzothiazol-5yl) bicyclo [2. 2. 1] hept-2-en-2-yl] methanamine [3- (5-methoxy-2-naphthyl) bicyclo [2. 2. 1] hept-2-en-2-yl] N, N-dimethylmethanamine
[3- (6-fluoro-l, 3-benzothiazol-2-yl) bicyclo [2. 2. 1] hept-2en-2-yl]-N, N-dimethylmethanamine (3- (4-chloro-1, 3-benzothiazol-2-yl) bicyclo [2. 2. 1] hept-2en-2-yl]-N, N-dimethylmethanamine [3- (6-methoxy-l, 3-benzothiazol-2-yl) bicyclo [2. 2. 1] hept2-en-2-yl]-N, N-dimethylmethanamine N, N-dimethyl [3- (l-naphthyl) bicyclo [2. 2. 1] hept-2-en-2yl] methanamine [3- (6-chloro-l-benzothien-2-yl) bicyclo [2. 2. 1] hept-2-en2-yl]-N, N-dimethylmethanamine [3- (4-methoxy-l, 3-benzothiazol-2-yl) bicyclo [2. 2. 1] hept2-en-2-yl]-N, N-dimethylmethanamine [3- (7-bromo-4-methoxy-l, 3-benzothiazol-2yl) bicyclo [2. 2. 1] hept-2-en-2-yl]-N, N-dimethylmethanamine N, N-dimethyl (3- [6- (trifluoromethyl)-l-benzothien-2yl] bicyclo [2. 2. 1] hept-2-en-2-yl} methanamine
[3- (6-chloro-l-benzothien-3-yl) bicyclo [2. 2. 1] hept-2-en2-yl]-N, N-dimethylmethanamine N, N-dimethyl (3- [6- (trifluoromethyl)-l-benzothien-3yl] bicyclo [2. 2. 1] hept-2-en-2-yl} methanamine [3- (4-fluoro-l-naphthyl) bicyclo [2. 2. 1] hept-2-en-2-yl] N, N-dimethylmethanamine N, N-dimethyl [3- (6-methyl-l-benzothien-2yl) bicyclo [2. 2. 1] hept-2-en-2-yl] methanamine 1- {[3- (2-naphthyl) bicyclo[2. 2. 1] hept-2-en-2yllmethyl) piperidine 4- { [3- (2-naphthyl) bicyclo [2. 2. 1] hept-2-en-2yllmethyl) morpholine l-methyl-4- { [3- (2-naphthyl) bicyclo [2. 2. 1] hept-2-en-2yl] methyl} piperazine 1- {[3- (2-naphthyl) bicyclo[2. 2. 1] hept-2-en-2yl] methyl} piperazine N-ethyl-N- {[3- (2-naphthyl) bicyclo[2. 2. 1] hept-2-en-2yl] methyl} ethanamine
4- (6-methoxy-2-naphthyl)-2-methyl-l- { [3- (2naphthyl) bicyclo [2. 2. 1] hept-2-en-2-yl] methyl} piperidine 2-methyl-l- { [3- (2-naphthyl) bicyclo [2. 2. 1] hept-2-en-2yllmethyl) pyrrolidine methyl (-l- { [3- (2-naphthyl) bicyclo [2. 2. 1] hept-2-en-2yl] methyl}-2-pyrrolidinyl) methyl ether (-l- { [3- (2-naphthyl) bicyclo [2. 2. 1] hept-2-en-2yl] methyl}-2-pyrrolidinyl) methanol N- (2, 5-Dimethyl) pyrrolidyl- [2- (2naphthyl) bicyclo [2. 2. 1]-2-hepten-3-yl] methylamine N- (2R-Hydroxymethyl) pyrrolidyl- [2- (2-naphthyl) bicyclo [2. 2. 1]-2-hepten-3-yl] methylamine N- (-Hydroxymethyl) pyrrolidyl- [2- (2-naphthyl) bicyclo [2. 2. 1]-2-hepten-3-yl] methylamine 1- {[3- (2-naphthyl) bicyclo[2. 2. 1] hept-2-en-2-yl] methyl}3-pyrrolidinol
N- (l- { [3- (2-naphthyl) bicyclo [2. 2. 1] hept-2-en-2yl] methyl}-3-pyrrolidinyl) acetamide 1- {[3- (6-fluoro-l-benzothien-3-yl) bicyclo[2. 2. 1] hept-2en-2-yl] methyl} pyrrolidine 1- {[3- (3-methyl-l-benzothien-5-yl) bicyclo[2. 2. 1] hept-2en-2-yl] methyl} pyrrolidine 2, 2-dimethyl-l- { [3- (2-naphthyl) bicyclo [2. 2. 1] hept-2-en2-yl] methyl} pyrrolidine N- { [3- (l-benzothien-7-yl) bicyclo [2. 2. 1] hept-2-en-2yl]methyl}-N-methyl-2-propen-l-amine [3- (l-benzothien-7-yl) bicyclo [2. 2. 1] hept-2-en-2-yl]-Nmethylmethanamine N, N-Pyrrolidyl- [2- (2-naphthyl) bicyclo [2. 2. 1]-2-hepten-3-yl] methanamine dimethyl-[3- (5-fluorobenzo[b]thiophen-2yl) bicyclo [2. 2. l] hept-2-en-2-yl] methanamine dimethyl-[3- (4-fluorobenzo[b]thiophen-2yl) bicyclo [2. 2. 1] hept-2-en-2-yl] methanamine
dimethyl- [3- (6-fluorobenzo [b] thiophen-2yl) bicyclo [2. 2. 1] hept-2-en-2-yl] methanamine dimethyl-[3- (7-fluorobenzo[b]thiophen-2yl) bicyclo [2. 2. 1] hept-2-en-2-yl] methanamine dimethyl- [3- (7-methoxybenzo [b] thiophen-2yl) bicyclo [2. 2. 1] hept-2-en-2-yl] methanamine (3- (6-fluorobenzo[b]thiophen-2-yl) bicyclo[2. 2. 1] hept-2en-2-yl) methyl) methanamine [3- (l, 3-benzothiazol-2-yl) bicyclo [2. 2. 1] hept-2-en-2-yl] N-methylmethanamine [3- (6-chloro-l, 3-benzothiazol-2-yl) bicyclo [2. 2. 1] hept-2en-2-yl]-N-methylmethanamine N-benzyl-N- { [3- (6-methoxy-2-naphthyl) bicyclo [2. 2. 1] hept2-en-2-yl] methyl}-N-methanamine ( (3- (benzo[b]thiophen-4-yl) bicyclo[2. 2. 1]-hept-2-en-2yl) methyl) dimethanamine dimethyl (2- (5-fluorobenzo[b] thiophen-2yl) bicyclo [3. 2. 1]-oct-2-en-3-yl) methanamine
N, N-dimethyl [2- (2-naphthyl) bicyclo [3. 2. 1] oct-2-en-3yl] methanamine N, N-dimethyl [2- (6-fluoro-2-naphthyl) bicyclo [3. 2. 1] oct2-en-3-yl] methanamine N, N-dimethyl [2- (6-fluoro-2-naphthyl) bicyclo [3. 2. 1] oct-2-en-3-yl] methanamine [2- (7-fluoro-l-benzothien-2-yl) bicyclo [3. 2. 1] oct-2-en-3yl]-N, N-dimethylmethanamine [2- (4-fluoro-l-benzothien-2-yl) bicyclo [3. 2. 1] oct-2-en-3yl]-N, N-dimethylmethanamine [2- (6-fluoro-l-benzothien-2-yl) bicyclo [3. 2. 1] oct-2-en-3yl]-N, N-dimethylmethanamine [2- (6-fluoro-l-benzothien-2yl) bicyclo [3. 2. 1] oct-2-en-3-yl]-N, N-dimethylmethanamine [2- (6-fluoro-l-benzothien-3-yl) bicyclo [3. 2. 1] oct-2-en-3yl]-N, N-dimethylmethanamine 2- {3- [ (dimethylamino) methyl] bicyclo [3. 2. 1] oct-2-en-2yl}-l-benzothiophene-6-carbonitrile
[2- (6-trifluoro-l-benzothien-3-yl) bicyclo [3. 2. 1] oct-2en-3-yl]-N, N-dimethylmethanamine N, N-dimethyl [3- (2-naphthyl) bicyclo [2. 2. 2] oct-2-en-2 yljmethanamine [3-(6-methoxy-2-naphthyl)bicyclo[2. 2. 2] oct-2-en-2-yl] N, N-dimethylmethanamine [3- (l-benzothien-3-yl) bicyclo [2. 2. 2] oct-2-en-2-yl]-N, Ndimethylmethanamine
6- {3-[ (dimethylamino) methyl]bicyclo[2. 2. 2] oct-2-en-2 yl} -2-naphthol [3-(6-fluoro-2-naphthyl)bicyclo[2. 2. 2] oct-2-en-2-yl] N, N-dimethylmethanamine [3-(6-fluoro-1-benzothien-3-yl)bicyclo[2. 2. 2] oct-2-en-2- yl]-N, N-dimethylmethanamine
l- { [3- (l-benzothien-5-yl) bicyclo [3. 2. 1] oct-2-en-2yl] methyl} pyrrolidine
l- { [3- (l-benzothien-5-yl) bicyclo [3. 2. 1] oct-2-en-2yl] methyl} azetidine l- { [3- (3-methyl-l-benzothien-5-yl) bicyclo [2. 2. 2] oct-2en-2-yl] methyl} pyrrolidine [3- (l-benzothien-7-yl) bicyclo [2. 2. 2] oct-2-en-2-yl]-Nmethylmethanamine [2- (l-benzothien-5-yl) bicyclo [3. 2. 1] oct-2-en-3-yl]-N, Ndimethylmethanamine 2- (l-benzothien-5-yl) bicyclo [3. 2. 1] oct-2-en-3-yl]-N, Ndimethylmethanamine 2- (l-benzothien-5-yl) bicyclo [3. 2. 1] oct-2-en-3-yl]-N, Ndimethylmethanamine [2- (l-benzothien-6-yl) bicyclo [3. 2. 1] oct-2-en-3-yl]-N, Ndimethylmethanamine [2- (l-benzothien-4-yl) bicyclo [3. 2. 1] oct-2-en-3-yl]-N, Ndimethylmethanamine [2- (1-benzothien-4-yl) bicyclo [3. 2. 1] oct-2-en-3-yl]-N, Ndimethylmethanamine
[2- (l-benzothien-7-yl) bicyclo [3. 2. 1] oct-2-en-3-yl]-N, Ndimethylmethanamine [2- (1-benzothien-7-yl) bicyclo [3. 2. 1] oct-2-en-3-yl]-N, Ndimethylmethanamine [2- (3-chloro-l-benzothien-5-yl) bicyclo [3. 2. 1] oct-2-en-3yl]-N, N-dimethylmethanamine N, N-dimethyl [2- (3-methyl-l-benzothien-5yl) bicyclo [3. 2. 1] oct-2-en-3-yl] methanamine N, N-dimethyl [2- (3-methyl-l-benzothien-5yl) bicyclo [3. 2. 1] oct-2-en-3-yl] methanamine N, N-dimethyl [2- (3-methyl-l-benzothien-7-yl) bicyclo [3. 2. 1] oct-2-en-3-yl] methanamine [3- (1-benzothien-5-yl) bicyclo [2. 2. 2] oct-2-en-2-yl]-N, Ndimethylmethanamine [3- (1-benzothien-6-yl) bicyclo [2. 2. 2] oct-2-en-2-yl]-N, Ndimethylmethanamine
[3- (3-chloro-l-benzothien-5-yl) bicyclo [2. 2. 2] oct-2-en-2yl]-N, N-dimethylmethanamine N, N-dimethyl [3- (3-methyl-l-benzothien-5-yl) bicyclo [2. 2. 2] oct-2-en-2-yl] methanamine [3- (l-benzothien-7-yl) bicyclo [2. 2. 2] oct-2-en-2-yl]-N, Ndimethylmethanamine [3- (l-benzothien-4-yl) bicyclo [2. 2. 2] oct-2-en-2-yl]-N, Ndimethylmethanamine N-methyl-N- { [2- (3-methyl-l-benzothien-5yl) bicyclo [3. 2. 1] oct-2-en-3-yl] methanamine [3- (6-fluoro-2-naphthyl) bicyclo [3. 2. 1] oct-2-en-2-yl]-Nmethylmethanamine N, N-dimethyl [3- (6- { [4- (trifluoromethyl) benzyl] oxy}-2naphthyl) bicyclo [2. 2. 2] oct-2-en-2-yl] methanamine [3- (6-methoxy-2-naphthyl) bicyclo [2. 2. 2] oct-2-en-2-yl] N, N-dimethylmethanamine [3- (6-butoxy-2-naphthyl) bicyclo [2. 2. 2] oct-2-en-2-yl] N, N-dimethylmethanamine
{3-[6- (benzyloxy)-2-naphthyl]bicyclo[2. 2. 2] oct-2-en-2yl}-N, N-dimethylmethanamine (3-t6- [ (4-bromobenzyl) oxyl-2-naphthyllbicyclo [2. 2. 2] oct2-en-2-yl)-N, N-dimethylmethanamine 4- { [ (6- {3- [ (dimethylamino) methyl] bicyclo [2. 2. 2] oct-2-en2-yl}-2-naphthyl) oxy] methyl} benzonitrile (3- {6- [ (3-chlorobenzyl) oxy]-2-naphthyl} bicyclo [2. 2. 2] oct-2-en-2-yl)-N, N-dimethylmethanamine N, N-dimethyl (3-f6- [ (4-methylbenzyl) oxy]-2naphthyl} bicyclo [2. 2. 2] oct-2-en-2-yl) methanamine (3- {6- [ (2, 6-dichlorobenzyl) oxy]-2-naphthyl} bicyclo [2. 2. 2] oct-2-en-2-yl)-N, N-dimethylmethanamine [3- (6-ethoxy-2-naphthyl) bicyclo [2. 2. 2] oct-2-en-2-yl] N, N-dimethylmethanamine (3- {6- [ (4-tert-butylbenzyl) oxy]-2-naphthyl} bicyclo [2. 2. 2] oct-2-en-2-yl)-N, N-dimethylmethanamine (3- {6- [ (2-chlorobenzyl) oxy]-2-naphthyl} bicyclo
[2. 2. 2] oct-2-en-2-yl)-N, N-dimethylmethanamine (3- {6- [ (4-fluorobenzyl) oxy]-2-naphthyl} bicyclo [2. 2. 2] oct-2-en-2-yl)-N, N-dimethylmethanamine N, N-dimethyl [3- (6-propoxy-2-naphthyl) bicyclo [2. 2. 2] oct2-en-2-yl] methanamine (3- {6-[ (4-methoxybenzyl) oxy]-2-naphthyl} bicyclo [2. 2. 2] oct-2-en-2-yl)-N, N-dimethylmethanamine N, N-dimethyl (3- {6- [ (4-nitrobenzyl) oxy]-2naphthyl} bicyclo [2. 2. 2] oct-2-en-2-yl) methanamine N, N-dimethyl[3- (6- {[4- (trifluoromethoxy) benzyl]oxy}-2naphthyl) bicyclo [2. 2. 2] oct-2-en-2-yl] methanamine The invention also includes processes for the production of compounds of the formula (I) above. One process for producing the compounds of formula (I) comprises dehydrating a compound of formula
preferably employing a dehydrating agent, such as for example trifluoroacetic acid or p-toluene sulfonic acid.
The reaction is preferably carried out in an organic solvent, such as for example dichloromethane, at a temperature of from 0 C to 100 C.
Compounds of formula (II) can be prepared, for example, by reaction of a Grignard reagent of formula R3 MgBr, conveniently prepared in situ, with a cyclic ketone of the formula
Alternatively, compounds of formula (II) can be prepared by reaction of a compound of formula (III) with a suitable lithium derivative of formula R3Li.
Such cyclic ketones can, in their turn, be prepared by
reacting the appropriate amine of formula HNR1R2 with a compound of formula
Compound (IV) can be made from the cyclic ketone by the Mannich reaction, to yield a compound of formula (III) in which Rl and R2 are both methyl, followed by quaternisation and elimination.
A further process for preparing compounds of formula (I), comprises reacting a compound of the formula
where R4 is a leaving group, with a suitable aryl metal complex that displaces R4 with the desired R3 group. The reaction is preferably carried out in an organic solvent at a temperature of from OOC to 100 C. A suitable leaving group is triflate.
It will be appreciated that substituents on the naphthyl or heterocyclyl ring can be introduced at the outset, or
in the final stages of the synthesis. Sometimes it will be convenient to convert one substituent to another as, for example, Cl-4 alkoxy to hydroxy, at an intermediate stage or in the final product.
As mentioned above, the compounds of the invention and their pharmaceutically acceptable salts have useful central nervous system activity. The compounds inhibit the uptake of neurotransmitters such as serotonin, dopamine and noradrenalin. They are surprisingly effective serotonin reuptake inhibitors, as evidenced by their displacement of [3H] citalopram at the binding sites on membranes derived from rat cortex, as in the test described below (see Example 29). In a similar test, also employing rat cortex membrane, the compounds displaced nisoxetine, demonstrating their ability to inhibit noradrenalin reuptake, see Journal of Pharmacology and Experimental Therapeutics Vol. 272, No. 3,1176-1186, 1995. The dopamine reuptake properties of the compounds of the invention are demonstrated in the test described in Molecular Pharmacology 45: 125-135, using membranes derived from rat striatum. In this test displacement of WIN 35,428 from its reuptake site, is measured.
Because of their profile of neurotransmitter reuptake properties, the compounds of the present invention are indicated for use in treating a variety of conditions such as depression, obesity, bulimia, alcoholism, pain, hypertension, ageing, senile dementia, Alzheimer's, memory loss, attention-deficit hyperactivity disorder, sexual dysfunction, Parkinsonism, anxiety, chronic fatigue syndrome, panic disorders, obsessive compulsive disorder, schizophrenia, gastrointestinal disorders, headache, cardiovascular disorders, smoking cessation, drug addiction including ***e abuse, emesis and sleep disorders.
The compounds of the invention are effective over a wide dosage range, the actual dose administered being dependent on such factors as the particular compound being used, the condition being treated and the type and size of mammal being treated. However, the dosage required will normally fall within the range of 0.01 to 20 mg/kg per day, for example in the treatment of adult humans, dosages of from 0.5 to 100 mg per day may be used.
The compounds of the invention will normally be administered orally or by injection and, for this purpose, the compounds will usually be utilised in the
form of a pharmaceutical composition. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
Accordingly the invention includes a pharmaceutical composition comprising as active ingredient a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof, associated with a pharmaceutically acceptable excipient. In making the compositions of the invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. The excipient may be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient.
Some examples of suitable excipients are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin syrup, methyl cellulose, methyl-and propylhydroxybenzoate, talc, magnesium stearate or oil. The compositions of the invention may, if desired, be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient.
Depending on the route of administration, the foregoing compositions may be formulated as tablets, capsules or suspensions for oral use and injection solutions or suspensions for parenteral use or as suppositories.
Preferably the compositions are formulated in a dosage unit form, each dosage containing from 0.5 to 100 mg, more usually 1 to 100 mg, of the active ingredient.
The following Examples illustrate the synthesis of the compounds of invention.
EXAMPLE 1 ()-3- (JW, JV-Dimethylamino) methylbicyclo [2. 2. 1heptan-2one To a solution of 81.8 mL of 2.0 M dimethylamine in THF (164 mmol) was added 3-methylene-bicyclo [2, 2, 1]heptan-2- one (10.0 mL, 81.9 mmol). The solution was stirred at room temperature for 24 h. The reaction mixture was then concentrated to give the crude title compound as an orange oil (13.50 g, 99% yield). IR (CHC13) 1732 cm-1.
Ion Spray MS 168 (M+H) +.
Similarly prepared were : (lR/S, 4R/S)-3- (N-pyrrolidyl) methylbicyclo [2. 2. 1] heptan2-one, FDMS m/e = 194 (M++H).
(lR/S, 4R/S)-3- (N-piperidinyl) methylbicyclo [2. 2. 1] heptan2-one, FDMS m/e = 208 (M++H).
(li/5, 4R/S)-3- (N-morpholino) methylbicyclo [2. 2. 1] heptan2-one, FDMS m/e = 210 (M++H).
(lR/S, 4R/S)-3- (N- (4-tert-butyloxycarbonylpiperazinyl)) methylbicyclo [2. 2. 1] heptan-2-one, FDMS m/e = 309 (M++H).
(lR/S, 4R/S)-3- (N- (4-methylpiperazinyl)) methylbicyclo [2. 2. 1] heptan-2-one, FDMS m/e = 223 (M++H).
(lR/S, 4R/S)-3- (N, N-diethyl) methylbicyclo [2. 2. 1] heptan-2- one, FDMS m/e = 196 (M++H).
CIS (lR/S, 4R/S)-3-(N-(4-(2-(6-methoxy)naphthyl)-2-methyl piperidinyl) ) methylbicyclo [2. 2. 1] heptan-2-one, FDMS m/e = 378 (M++H). trans- (lR/S, 4R/S)-3- (N- (4- (2- (6-methoxy) naphthyl) -2 Methylpiperidinyl) ) methylbicyclo [2. 2. 1] heptan-2-one, FDMS m/e = 378 (M++H).
(lR/S, 4R/S)-3- (N- (2-methyl) pyrrolidyl) methyl
bicyclo [2. 2. 1] heptan-2-one, FDMS m/e = 208 (M++H).
(lR/5, 4R/S)-3- (N- (2S-hydroxymethyl) pyrrolidyl) methylbicyclo [2. 2. 1] heptan-2-one, FDMS m/e = 224 (M++H).
(lR/S, 4R/S)-3- (N- (2R-hydroxymethyl) pyrrolidyl) methylbicyclo [2. 2. 1] heptan-2-one, FDMS m/e = 224 (M++H).
(lR/S, 4R/S)-3- (N- (2S-methoxymethyl) pyrrolidyl) methyl bicyclo [2. 2. 1] heptan-2-one, FDMS m/e = 238 (M++H).
(lR/S, 4R/S)-3- (N- (2R-methoxymethyl) pyrrolidyl) methyl bicyclo [2. 2. 1] heptan-2-one, FDMS m/e = 238 (M++H).
(lR/S, 4R/S)-3- (N- (3-hydroxy) pyrrolidyl) methyl bicyclo [2. 2. 1] heptan-2-one, FDMS m/e = 210 (M++H).
(lR/S, 4R/S)-3- (N- (2, 5-dimethyl) pyrrolidyl) methyl bicyclo [2. 2. 1] heptan-2-one, FDMS m/e = 222 (M++H).
(lR/S, 4R/S)-3- (N- (3-S-acetamido) pyrrolidyl) methyl bicyclo [2. 2. 1] heptan-2-one, FDMS m/e = 251 (M++H).
EXAMPLE 2 (+/-)-3- (2V, -Dimethylamino) methyl-2- (4methoxybenzo [b] thiophen-2-yl) bicyclo [2. 2. 1] heptan-2-ol.
To a solution of 4-methoxybenzo[b] thiophene (0. 500 g, 3.04 mmol) in dry THF (10.0 mL) at-78 Oc was added 1.6 M n-BuLi in hexanes (2.28 mL, 3.65 mmol). The solution was stirred at-78 2C for 45 min and then 3- (N, Ndimethylamino) methyl [2, 2, 1] heptan-2-one (0.509 g, 3.04 mmol) in THF (3 mL) was added via a cannulla at-78 C.
The reaction mixture was stirred at-78 2C for 1. 75 h.
The reaction was then quenched with 15 mL of saturated aqueous NH4Cl solution. The mixture was extracted with
EtOAc (2 x 100 mL). The combined organic layers were dried over MgSO4 and filtered. The filtrate was concentrated and purified by medium pressure chromatography (silica gel, 2% (2.0 M NH3 in MeOH)/CH2Cl2) to give the title compound as a white solid (0.283 g, 28%). IR (KBr) 3100 (br) cm-1. EI+ MS
228 (M-103) + (base peak) ; 331 (M) +.
Similarly prepared were : (lR/S, 4R/S)-3- (N-pyrrolidyl) methyl-2- (2-naphthyl) bicyclo [2. 2. 1] heptan-2-ol FDMS m/e = 322 (M++H).
(lR/S, 4R/S)-3- (N-piperidinyl) methyl-2- (2-naphthyl) bicyclo [2. 2. 1] heptan-2-ol, FDMS m/e = 336 (M++H).
(lR/S, 4R/S)-3- (N-morpholino) methyl-2- (2-naphthyl) bicyclo [2. 2. 1] heptan-2-ol, FDMS m/e = 338 (M++H).
(lR/S, 4R/S)-3- (N- (4-tert-butyloxycarbonylpiperazinyl)) methyl-2- (2-naphthyl) bicyclo [2. 2. 1] heptan-2-ol, FDMS m/e = 437 (M++H).
(lR/S, 4R/S)-3-(N-(4-methylpierazinyl))methyl-2-(2naphthyl) bicyclo [2. 2. 1] heptan-2-ol, FDMS m/e = 351 (M++H).
(lR/S, 4R/S)-3-(N,N-diethylamino)methyl-2-(2-naphthyl) bicyclo [2. 2. 1] heptan-2-ol, FDMS m/e = 324 (M++H). cis- (1R/S, 4R/S)-3- (N- (4- (2- (6-methoxy) naphthyl)-2methylpiperidinyl)) methyl-2- (2-naphthyl) bicyclo [2. 2. 1] heptan-2-ol, FDMS m/e = 506 (M++H).
trans- (lR/S, 4R/S)-3- (N- (4- (2- (6-methoxy) naphthyl)-2methylpiperidinyl)) methyl-2- (2-naphthyl) bicyclo [2. 2. 1] heptan-2-ol, FDMS m/e = 506 (M++H).
(lR/S, 4R/S)-3-(N-(2-methyl) pyrrolidyl) methyl-2- (2naphthyl) bicyclo [2. 2. 1] heptan-2-ol, FDMS m/e = 336 (M++H).
3- (N- (2S-hydroxymethyl) pyrrolidyl) methyl-2- (2-naphthyl) bicyclo [2. 2. 1] heptan-2-ol, FDMS m/e = 352 (M++H).
3- (N- (2R-hydroxymethyl) pyrrolidyl) methyl-2- (2-naphthyl) bicyclo [2. 2. 1] heptan-2-ol, FDMS m/e = 352 (M++H).
(1R/S,4R/S)-3-(N-(2S-methoxymethyl) pyrrolidyl) methyl-2 (2-naphthyl) bicyclo [2. 2. 1] heptan-2-ol, FDMS m/e = 366 (M++H).
(1R/S,4R/S)-3-(N-(2R-methoxymethyl) pyrrolidyl) methyl-2 (2-naphthyl) bicyclo [2. 2. 1] heptan-2-ol, FDMS m/e = 366 (M++H).
(lR/, 4R/)-3- (N- (3-hydroxy) pyrrolidyl) methyl-2-(2naphthyl) bicyclo [2. 2. 1] heptan-2-ol, MS m/e = 338 (M++H).
(lR/S, 4R/S)-3-(N-(2,5-dimethyl) pyrrolidyl) methyl-2- (2naphthyl) bicyclo [2. 2. 1] heptan-2-ol, FDMS m/e = 350 (M++H).
3- (N- (3-S-acetamido) pyrrolidyl) methyl-2- (2-naphthyl) bicyclo [2. 2. 1] heptan-2-ol, FDMS m/e = 379 (M++H).
EXAMPLE 3 (+/-) Trifluoromethanesulfonic Acid 3 Dimethylaminomethylbicyclo [2. 2. 1] hept-2-en-2-yl Ester.
To a cooled (-78 OC) solution of diisopropylamine (11.8 mL, 84.5 mmol) in anhydrous THF (85 mL) was added 1.6 M n-BuLi in hexanes (52.8 mL, 84.5 mmol). The solution was stirred at-78 Oc for 1 h. The dry ice bath was removed and the solution was stirred for an additional 0.5 h. The solution was then recooled to-78 oc and (±)-3- (N, N-dimethylamino) methylbicyclo [2. 2. 1] heptan-2-one (13.5 g, 80.5 mmol) in anhydrous THF (85 mL) was added via a cannulla over a period of 15 min. The solution was stirred at-78 Oc for 35 min. N Phenyl-bis (trifluoromethanesulfonimide) (30.2 g, 84.5 mmol) in anhydrous THF (85 mL) was added to the reaction mixture via a canulla over a period of 20 min. at-78 OC. The resulting solution was allowed to slowly warm to room temperature overnight. The reaction mixture was then concentrated under reduced pressure. The residue was diluted with CH2Cl2 (75 mL). The mixture was then
eluted on a pad of neutral alumina using 5% EtOAc in hexanes (3 L) as eluent. The collected fraction was concentrated and purified by medium pressure chromatography (silica gel, 1.5-2. 0% (3.5 M NH3 in
MeOH)/CH2Cl2) to give the title compound as a yellow oil (17. 4 g, 72%). IR (CHCI3) 1419, 1141 cm-1. Ion Spray MS 300 (M+H) +.
EXAMPLE 4
(+/-) (N, N-Dimethylamino) methyl-2- (6fluorobenzo[b]thiophen-3-yl) bicyclo[2. 2. 1] heptan-2-ol To a solution of crude 3-bromo-6-fluorobenzo[b]thiophene (0.960 g, 4.15 mmol) in anhydrous THF (20 mL) was added dibromoethane (0.358 ml, 4.15 mmol) and magnesium turnings (0.202 g, 8.30 mmol). The solution was stirred at reflux for 2 h. or until the magnesium was consumed.
The reaction mixture was removed from the heat and (+ ) (N, N-dimethylamino) methylbicyclo [2. 2. 1] heptan-2-one (0.764 g, 4.57 mmol) in anhydrous THF (6 mL) was added to the solution at room temperature. The solution was stirred for 20 h. The reaction was quenched with saturated aqueous NH4C1 solution. (30 mL). The mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over MgSO4 and concentrated.
The residue was purified by medium pressure chromatography (silca gel, 2.5% (2.0 M NH3 in
MeOH)/CH2C12) to give the title compound as a white semi solid (0.271 g, 20%). Ion Spray MS 320 (M+H) +, 290 (base peak) (M-29) +.
EXAMPLE 5 3- [ (Dimethylamino) methyl]-2- (6-fluoro-2-naphthyl) bicyclo [2. 2. 1] heptan-2-ol The enantiomers of 3- [ (dimethylamino) methyl]-2- (6fluoro-2-naphthyl) bicyclo [2. 2. 1] heptan-2-ol were separated by chiral preparative chromatography, using a CHIRALPAK-AD colunm, and a mixture of Hexane/Ethanol 80/20 as the eluant.
EXAMPLE 6
(+/-) Dimethyl- [3- (4-methoxybenzo [b] thiophen-2yl) bicyclo [2. 2. 1] hept-2-en-2-yl] methylamine hydrochloride To a solution of (+/-) (N, N-dimethylamino) methyl-2- (4 methoxybenzo[b]thiophen-2-yl) bicyclo[2. 2. 1] heptan-2-ol (0.277 g, 0.835 mmol) in dry CH2Cl2 (7 mL) at 0 C was added 2 mL of trifluoroacetic acid. The solution was
stirred at 0 2C for 3 h. The reaction was then quenched with saturated aqueous Nah03 solution (30 mL). The mixture was extracted (2 x 40 mL) with CH2C12. The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by medium
pressure chromatography (silica gel, 3% (2. 0 M NH3 in MeOH)/CH2C12) to give the free base of the title compound as an off-white semi-solid (0.243 g, 93%). The hydrochloride salt was prepared with 1.0 equiv. of HC1 in EtOAc. m. p. (HCl) 239-242 OC. FDMS m/e = 313 M+.
Similarly prepared were: N, N-dimethyl[3-(2-naphthyl)bicyclo[2. 2. 1]hept-2-en-2yl] methanamine hydrochloride, mp 226.3-227. 3 C
[3- (l-benzothien-2-yl) bicyclo [2. 2. 1] hept-2-en-2-yl]-N, Ndimethylmethanamine hydrochloride, FIA POS MS (M+H, 284) [3- (3-bromo-l-benzothien-2-yl) bicyclo [2. 2. 1] hept-2-en-2 yl]-N, N-dimethylmethanamine hydrochloride, mp 1092, FIA POS MS (M+H, 362/364) [3-(6-methoxy-2-naphthyl)bicyclo[2. 2. 1]hept-2-en-2-yl] N, N-dimethylmethanamine hydrochloride, mp 201.7-202. 52C [3- [l, l'-biphenyl]-4-ylbicyclo [2. 2. 1] hept-2-en-2-yl] N, N-dimethylmethanamine hydrochloride, mp 226.6-227. 92C [3- (l, 3-benzodioxol-5-yl) bicyclo [2. 2. 1] hept-2-en-2-yl]- N, N-dimethylmethanamine hydrochloride, mp 222.5 OC
6- (3-[ (dimethylamino) methyl]bicyclo[2. 2. 1] hept-2-en-2yl}-2-naphthol hydrochloride, mp 222. 9-224. 52C [3- (6-bromo-2-naphthyl) bicyclo [2. 2. 1] hept-2-en-2-yl] N, N-dimethylmethanamine hydrochloride, mp 225. 8-226. 62C [3- (l-benzofuran-2-yl) bicyclo [2. 2. 1] hept-2-en-2-yl]-N, Ndimethylmethanamine hydrochloride, mp 241. 5-242. 6 2C [3- (6-fluoro-2-naphthyl) bicyclo [2. 2. 1] hept-2-en-2-yl] N, N-dimethylmethanamine hydrochloride, mp 223. 4-224. 52C N, N-dimethyl-3- (3-pyridinyl) bicyclo [2. 2. 1] hept-2-en-2yl] methanamine dihydrochloride, decomposes after 225oc (1-benzothien-5-yl) bicyclo [2. 2. 1] hept-2-en-2-yl]-N, Ndimethylmethanamine hydrochloride, mp 227. 5-228. 52C [3- (l-benzothien-3-yl) bicyclo [2. 2. 1] hept-2-en-2-yl]-N, Ndimethylmethanamine hydrochloride, mp 205. 0-206. 62C N, N-dimethyl [3- (3-quinolinyl) bicyclo [2. 2. 1] hept-2-en-2yl] methanamine dihydrochloride, mp 246. 4-248. 92C
N, N-dimethyl [3- (5-methyl-l-benzothien-2yl) bicyclo [2. 2. 1] hept-2-en-2-yl] methanamine hydrochloride, mp 231.6-232. 52C N, N-dimethyl[3-(6-methyl-2-naphthyl)bicyclo[2. 2. 1] hept-
2-en-2-yl] methanamine, maleic acid, mp 171-172il [3- (l-benzothien-6-yl) bicyclo [2. 2. 1] hept-2-en-2-yl]-N, Ndimethylmethanamine, maleic acid, mp 185-187 2C [3- (6-chloro-1, 3-benzothiazol-2-yl) bicyclo [2. 2. 1] hept-2 en-2-yl]-N, N-dimethylmethanamine succinate, FIA POS MS (M+H, 321.0) N, N-dimethyl {3-[6-(methylsulfanyl)-2naphthyl]bicyclo[2. 2. 1] hept-2-en-2-yl} methanamine , maleic acid, MS ESP+ (M+, 324.1) [3-(6-methoxy-1-benzothien-2-yl)bicyclo[2. 2. 1] hept-2-en- 2-yl]-N, N-dimethylmethanamine hydrochloride, Ion Spray MS 269 (M-44 (-N (CH3) 2))+ [3-(5-methoxy-1-benzothien-2-yl)bicyclo[2. 2. 1]hept-2-en2-yl]-N, N-dimethylmethanamine hydrochloride, FDMS m/e 314 M+
[3- (8-methoxy-2-naphthyl) bicyclo [2. 2. 1] hept-2-en-2-yl] N, N-dimethylmethanamine, maleic acid, MS ESP+ (M+, 308. 1) N, N-dimethyl [3- (2-quinolinyl) bicyclo [2. 2. 1] hept-2-en-2yl] methanamine succinate, MS ESP+ (M+ 279. 0) [3- (4-isoquinolinyl) bicyclo [2. 2. 1] hept-2-en-2-yl]-N, Ndimethylmethanamine succinate, MS ESP+ (M+ 279. 0) N, N-dimethyl [3- (6-quinolinyl) bicyclo [2. 2. 1] hept-2-en-2yl] methanamine dihydrochloride, MS ESP+ (M+ 279. 0) N, N-dimethyl [3- (2-quinolinyl) bicyclo [2. 2. 1] hept-2-en-2yljmethanamine dihydrochloride, MS ESP+ (M+ 279. 0) [3- (4-isoquinolinyl) bicyclo [2. 2. 1] hept-2-en-2-yl]-N, Ndimethylmethanamine dihydrochloride, MS ESP+ (M+ 279. 0) N, N-dimethyl [3- (8-quinolinyl) bicyclo [2. 2. 1] hept-2-en-2yljmethanamine dihydrochloride, MS ESP+ (M+ 279. 0) N, N-dimethyl [3- (5-quinolinyl) bicyclo [2. 2. 1] hept-2-en-2yl] methanamine dihydrochloride, MS ESP+ (M+ 279. 0)
[3- (6-fluoro-l-benzothien-3-yl) bicyclo [2. 2. 1] hept-2-en2-yl]-N, N-dimethylmethanamine hydrochloride, Ion Spray MS 302 (M+H) \ 257 (M-44 (-N (CH3) 2)) + N, N-dimethyl [3- (2-methyl-6quinolinyl) bicyclo [2. 2. 1] hept-2-en-2-yl]methanamine dihydrochloride, MS ESP+ (M+, 293.0) N, N-dimethyl[3-(4-methyl-2quinolinyl) bicyclo [2. 2. 1] hept-2-en-2-yl] methanamine dihydrochloride, , MS ESP+ (M+, 293.2)
N, N-dimethyl[3- (2-methyl-l, 3-benzothiazol-5yl) bicyclo [2. 2. 1] hept-2-en-2-yl] methanamine hydrochloride,, FIA POS MS (M+H, 299. 2) [3- (5-methoxy-2-naphthyl) bicyclo [2. 2. 1] hept-2-en-2-yl] N, N-dimethylmethanamine, maleic acid, MS ESP+ (M+, 308. 2) [3- (6-fluoro-1, 3-benzothiazol-2-yl) bicyclo [2. 2. 1] hept-2 en-2-yl]-N, N-dimethylmethanamine hydrochloride, MS (M+H , 303.1) [3-(4-chloro-1, 3-benzothiazol-2-yl) bicyclo [2. 2. 1] hept-2- en-2-yl]-N, N-dimethylmethanamine hydrochloride, MS ESP+ (M+, 319.0)
[3- (6-methoxy-l, 3-benzothiazol-2-yl) bicyclo [2. 2. 1] hept2-en-2-yl]-N, N-dimethylmethanamine hydrochloride, FIA POS MS (M+H, 315. 3) N, N-dimethyl [3- (l-naphthyl) bicyclo [2. 2. 1] hept-2-en-2yl] methanamine, maleic acid, mp 142. 9-143. 72C [3- (6-chloro-l-benzothien-2-yl) bicyclo [2. 2. 1] hept-2-en2-yl]-N, N-dimethylmethanamine hydrochloride, mp 235-2372C [3- (4-methoxy-l, 3-benzothiazol-2-yl) bicyclo [2. 2. 1] hept2-en-2-yl]-N, N-dimethylmethanamine hydrochloride, MS ESP+ (M+, 314. 0) [3- (7-bromo-4-methoxy-l, 3-benzothiazol-2yl) bicyclo [2. 2. 1] hept-2-en-2-yl]-N, N-dimethylmethanamine hydrochloride, FIA POS MS (M+H, 395. 0) N, N-dimethyl {3- [6- (trifluoromethyl)-l-benzothien-2yl] bicyclo [2. 2. 1] hept-2-en-2-yl} methanamine hydrochloride, mp 237-2392C [3- (6-chloro-l-benzothien-3-yl) bicyclo [2. 2. 1] hept-2-en2-yl]-N, N-dimethylmethanamine hydrochloride, FIA Pos MS (M+H, 318. 1)
N, N-dimethyl {3- [6- (trifluoromethyl)-l-benzothien-3yl] bicyclo [2. 2. 1] hept-2-en-2-yl} methanamine hydrochloride, mp 169-171 2C [3- (4-fluoro-l-naphthyl) bicyclo [2. 2. 1] hept-2-en-2-yl] N, N-dimethylmethanamine hydrochloride, mp 245.5-247. 42C
N, N-dimethyl [3- (6-methyl-l-benzothien-2yl) bicyclo [2. 2. 1] hept-2-en-2-yl] methanamine hydrochloride, mp 228-230QC 1- {[3- (2-naphthyl) bicyclo[2. 2. 1] hept-2-en-2 yl]methyl}piperidine hydrochloride, FDMS m/e = 318 (M++H of free base).
4- { [ (lR, 4S)-3- (2-naphthyl) bicyclo [2. 2. 1]hept-2-en-2yl]methyl}morpholine hydrochloride, FDMS m/e = 320 (M++H of free base). l-methyl-4- { [3- (2-naphthyl) bicyclo [2. 2. 1] hept-2-en-2- yl] methyl} piperazine hydrochloride, FDMS m/e = 333 (M++H of free base).
1- {[3- (2-naphthyl) bicyclo[2. 2. 1] hept-2-en-2 yllmethyl) piperazine dihydrochloride, FDMS m/e = 319 (M++H of free base).
N-ethyl-N-{[3-(2-naphthyl)bicyclo[2. 2. 1] hept-2-en-2- yl]methyl}ethanamine hydrochloride, FDMS m/e = 305 (M+ of free base).
4- (6-methoxy-2-naphthyl)-2-methyl-l- { [ (lR, 4S)-3- (2naphthyl) bicyclo [2. 2. 1] hept-2-en-2-yl] methyl} piperidine hydrochloride, FDMS m/e = 488 (M+ of free base).
4- (6-methoxy-2-naphthyl)-2-methyl-l- { [ (lR, 4S)-3- (2naphthyl) bicyclo [2. 2. 1] hept-2-en-2-yl] methyl} piperidine hydrochloride, FDMS m/e = 488 (M+ of free base).
2-methyl-l- { [3- (2-naphthyl) bicyclo [2. 2. 1] hept-2-en-2 yl]methyl} pyrrolidine hydrochloride, FDMS m/e = 318 (M++H of free base).
Methyl ((2R)-1-{[3-(2-naphthyl)bicyclo[2. 2. 1]hept-2-en 2-yl] methyl}-2-pyrrolidinyl) methyl ether hydrochloride, FDMS m/e = 348 (M++H of free base). (X [D] 589 = 160 (c = 0.5, methanol).
Methyl ( (2S)-1- { [3- (2-naphthyl) bicyclo [2. 2. 1] hept-2-en2-yl] methyl}-2-pyrrolidinyl) methyl ether hydrochloride, FDMS m/e = 348 (M++H of free base). a [D] 5g9 =-171. 4 (c = 0. 56, methanol).
( (2S)-l- { [3- (2-naphthyl) bicyclo [2. 2. 1] hept-2-en-2yl] methyl}-2-pyrrolidinyl) methanol hydrochloride, FDMS m/e = 334 (M++H of free base). a [D] 589 =-183 (c = 0. 59, methanol).
( (2R)-1- { [3- (2-naphthyl) bicyclo [2. 2. 1] hept-2-en-2yl] methyl}-2-pyrrolidinyl) methanol hydrochloride, FDMS m/e = 334 (M++H of free base). a [D] s89 =-15. 09 (c = 0. 53 , methanol).
N- (2, 5-dimethyl) pyrrolidyl- [ (lR/, 4/)-2- (2naphthyl) bicyclo [2. 2. 1]-2-hepten-3-yl] methylamine hydrochloride, FDMS m/e = 332 (M++H of free base).
N- (2R-hydroxymethyl) pyrrolidyl- [2- (2-naphthyl) bicyclo [2. 2. 1]-2-hepten-3-yl] methylamine hydrochloride, FDMS m/e = 334 (M++1 of free base). a [D] 5g9 = 182. 8 (c = 0. 58 , methanol).
N- (2R-hydroxymethyl) pyrrolidyl- [2- (2-naphthyl) bicyclo
[2. 2. 1]-2-hepten-3-yl] methylamine hydrochloride, FDMS m/e = 334 (M++H of free base). a [D] 5g9 = 17. 86 (c = 0. 56 , methanol).
1- {[3- (2-naphthyl) bicyclo[2. 2. 1]hept-2-en-2-yl]methyl}3-pyrrolidinol hydrochloride, FDMS m/e = 320 (M++H of free base).
N- ( (3S)-1- {[3- (2-naphthyl) bicyclo[2. 2. 1] hept-2-en-2yl] methyl}-3-pyrrolidinyl) acetamide hydrochloride, FDMS m/e = 361 (M++H of free base). a [D] 5g9 =-49. 06 (c = 0. 53 , methanol). Mp 122-124 oc.
N- ( (3R)-l- { [3- (2-naphthyl) bicyclo [2. 2. 1] hept-2-en-2yl] methyl}-3-pyrrolidinyl) acetamide hydrochloride, FDMS m/e = 361 (M++H of free base). a [D] 5g9 = 50. 10 (c = 0. 50 , methanol). Mp 124-126 oc.
1-{[3-(6-fluoro-1-benzothien-3-yl)bicyclo[2. 2. 1] hept-2- en-2-yl]methyl} pyrrolidine hydrochloride, FIA POS MS (M+H, 328.2) 1-{[3-(3-methyl-1-benzothien-5-yl)bicyclo[2. 2. 1] hept-2- en-2-yl]methyl} pyrrolidine hydrochloride, FIA POS MS (M+H, 324.1),
2, 2-dimethyl-l- { [3- (2-naphthyl) bicyclo [2. 2. 1] hept-2-en2-yl] methyl} pyrrolidine hydrochloride, FIA POS MS (M+H, 332. 2), N- { [3- (1-benzothien-7-yl) bicyclo [2. 2. 1] hept-2-en-2yl] methyl}-N-methyl-2-propen-l-amine hydrochloride, FIA POS MS (M+H, 310. 1), [3- (l-benzothien-7-yl) bicyclo [2. 2. 1] hept-2-en-2-yl]-Nmethylmethanamine hydrochloride, FIA POS MS (M+H, 270. 1) N, N-pyrrolidyl- [ (l/, 4/)-2- (2-naphthyl) bicyclo [2. 2. 1]-2-hepten-3-yl] methylamine hydrochloride, FDMS m/e = 304 (M++H of free base).
EXAMPLE 7 (+/-)-Dimethyl- [3- (5-fluorobenzo [b] thiophen-2yl) bicyclo [2. 2. 1] hept-2-en-2-yl] methylamine hydrochloride.
To a cooled solution (-78 OC) of 5-fluorobenzo [b]thiophene (1. 00 g, 6. 57 mmol) in anhydrous THF (20 mL) was added 1. 6 M n-BuLi in hexanes (4. 11 mL, 6. 57 mmol). The resulting solution was stirred at-78 C for 45 min. The cold bath was removed and 0. 5 M zinc chloride in toluene (13. 1 mL, 6. 57 mmol) was added and
the mixture was stirred for 15 min. A slurry of (±)trifluoromethanesulfonic acid 3-dimethylaminomethyl bicyclo [2. 2. 1] hept-2-en-2-yl ester (1.48 g, 4.93 mmol), triphenylarsine (0.201 g, 0.657 mmol) and tris (dibenzylideneacetone) dipalladium (O) (0.301 g, 0.329 mmol) in anhydrous DMF (20 mL) was added to the reaction mixture via a canulla at room temperature. The reaction mixture was heated to reflux and stirred for 3 days.
The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. Xylenes were used to remove azeotropically the residual DMF. The residue was then partitioned between CH2Cl2 (70 mL) and H2O (20 mL). The layers were separated, and the aqueous layer was extracted with CH2C12 (1 x 100 mL). The combined
organic layers were dried over MgSO4 and concentrated.
The residue was purified by medium pressure chromatography (silica gel, 2% (2.0 M NH3 in MeOH)/CH2C12) to give the free base of the title compound as a clear oil (0.416 g, 28%). The hydrochloride salt was prepared with 1.0 equiv. of HC1 in EtOAc. Ion Spray MS (HC1) 302 (M+H) +, 257 (M-44 (-N (CH3) 2)) +.
Similarly prepared were:
(+/-)-dimethyl- [3- (4-fluorobenzo [b] thiophen-2yl) bicyclo [2. 2. 1] hept-2-en-2-yl] methylamine
Hydrochloride, Ion Spray MS (HC1) 302 (M+H) +, 257 (M44 (-N (CH3) 2)) + (+/-)-dimethyl- [3- (6-fluorobenzo [b] thiophen-2yl) bicyclo [2. 2. 1] hept-2-en-2-yl] methylamine Hydrochloride, FDMS m/e = 301 M+ (+/-)-dimethyl- [3- (7-fluorobenzo [jb] thiophen-2yl) bicyclo [2. 2. 1] hept-2-en-2-yl] methylamine Hydrochloride, Ion Spray MS (HC1) 302 (M+H) +, 257 (base peak) (M-44 (-N (CH3) 2))", 258 (M-43) EXAMPLE 8 (+/-)-Dimethyl- [3- (7-methoxybenzo [b] thiophen-2yl) bicyclo [2. 2. 1] hept-2-en-2-yl] methylamine hydrochloride A slurry containing 7-methoxybenzo[b]thiophene-2boronic acid (0. 500 g, 2. 40 mmol), trifluoromethane sulfonic acid 3-dimethylaminomethylbicyclo [2. 2. 1] hept-2en-2-yl ester (0. 504 g, 1. 68 mmol), lithium chloride (0. 214 g, 5. 05 mmol), tetrakis (triphenylphosphine) palladium (O) (0. 099, 0. 097 mmol) and 2. 0 N Na2CO3 (2. 40 mL, 4. 81 mmol) in 1, 2-dimethoxyethane (6 mL) was heated to reflux and stirred for 2h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in CH2C12
(20 mL), 2. 0 N Na2CO3 (20 mL) and conc. NH40H (1 mL).
The layers were separated and the aqueous layer was extracted with CH2Cl2 (1 x 30 mL). The organic layers were combined and dried over MgSO4 and concentrated.
The residue was purified by medium pressure chromatography (silica gel, 1-3% (3.5 M NH3 in MeOH)/CH2Cl2) to give the free base of the title compound as a brown semi-solid (0.036 g, 7%). The hydrochloride
salt was prepared with 1. 0 equiv. of HC1 in EtOAc. m. p.
232-235 C ; FDMS m/e = 313 M+.
EXAMPLE 9 (+/-)-3- (N-Benzyl-N-methylamino) methylbicyclo [2. 2. 1] heptan-2-one
To a solution of 3-methylene-bicyclo [2. 2. 1] heptan 2-one (6.00 mL, 49.0 mmol) in anhydrous THF (55 mL) was added N-benzylmethylamine. The solution was stirred at room temperature for 7 days. The reaction mixture was then concentrated under reduced pressure. The residue was purified by medium pressure chromatography (silica gel, 2% (2.0 M NH3 in MeOH)/CH2C12) to give the title compound as a yellow oil (11.48 g, 96%). Ion Spray MS 244 (M+H) + EXAMPLE 10
(+/-)-3- (N-Benzyl-N-methylamino) methyl-2- (6fluorobenzo [b] thiophen-2-yl) bicyclo [2. 2. 1] heptan-2-ol.
To a solution of a 1 : 6 mixture of 4-and 6fluorobenzo[b]thiophene (1. 00 g, 6. 57 mmol) and TMEDA (4. 96 mL, 32. 9 mmol) in dry THF (20 mL) at-78 2C was added 1. 6 M n-BuLi in hexanes (4. 52 mL, 7. 23 mmol). The solution was stirred at-78 QC for 55 min, and then 3 (N-benzyl-N-methylamino) methylbicyclo [2. 2. 1] heptan-2-one (1. 60 g, 6. 57 mmol) in THF (4 mL) was added via a canulla at-78=C. The resulting bright red reaction mixture was stirred at-78=C for 1. 75 h. The reaction was then quenched with 30 mL of saturated aqueous NH4Cl solution. The mixture was extracted with CH2C12 (2 x 100 mL). The combined organic layers were dried over MgSO4 and filtered. The filtrate was concentrated and purified by medium pressure chromatography (silica gel, 5% EtOAc in hexanes) to give the title compound as a clear semi-solid (1. 27 g, 49%). IR (CHC13) 3200 (br) cm-l Ion Spray MS 396 (M+H) +.
EXAMPLE 11 (+/-)-2- (6-Fluorobenzo[b]thiophen-2-yl)-3- (Nmethylamino) methylbicyclo [2. 2. 11heptanol To a solution of (±)-3- (N-benzyl-Nmethylamino) methyl-2- (6-fluorobenzo [b] thiophen-2yl) bicyclo [2. 2. 1] heptan-2-ol (292 mg, 0. 738 mmol) in a
1 : 1 THF : EtOH mixture (5 mL) was added 10% Pd/C (300 mg).
The black slurry was stirred vigorously under an H2 atmosphere for 4 days. The slurry was diluted with EtOH, filtered over a pad of diatomaceous earth, and washed with EtOH. The filtrate was concentrated and the residue was purified by medium pressure chromatography (silica gel, 3% (2.0 M NH3 in MEOH)/CH2Cl2) to give the title compound as a white solid (0.031 g, 14%). Ion Spray MS 306 (M+H) +, 245 (base peak) (M-60) +.
EXAMPLE 12
(+/-)- ( (3- (6-Fluorobenzo [b] thiophen-2yl) bicyclo [2. 2. 1] hept-2-en-2-yl) methyl) methylamine hydrochloride To a solution of (±)-2- (6-fluorobenzo[b]thiophen2-yl)-3- (N-methylamino) methylbicyclo [2. 2. 1] heptan-2-ol (0.029 g, 0.093 mmol) in dry CH2C12 (1.0 mL) at 0 2C was added 0.4 mL of trifluoroacetic acid. The solution was stirred at 0 Oc for 2 h. The reaction was then quenched with saturated aqueous NaHCO3 solution (7 mL). The mixture was extracted with CH2C12 (2 x 25 mL). The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by medium pressure chromatography (silica gel, 3% (2.0 M NH3 in MeOH)/CH2Cl2) to give the free base of the title compound as a brown semi-solid (0.021 g, 78%). The hydrochloride
salt was prepared with 1. 0 equiv. of HC1 in EtOAc. FDMS (HC1) m/e = 287 M+ Similarly prepared were : [ (lR, 4S)-3- (l, 3-benzothiazol-2-yl) bicyclo [2. 2. 1] hept-2en-2-yl]-N-methylmethanamine succinate, MS ESP+ (M+, 305. 0) [ (lR, 4S)-3- (6-chloro-1, 3-benzothiazol-2yl) bicyclo [2. 2. 1] hept-2-en-2-yl]-N-methylmethanamine succinate, FIA POS MS (M+H 271. 0) N-benzyl-N- {[3- (6-methoxy-2-naphthyl) bicyclo[2. 2. 1] hept2-en-2-yl]methyl}-N-methylamine hydrochloride, mp 1781802C EXAMPLE 13 (4-Bromobenzo[b]thiophen-2-yl) trimethylsilane Into a stirred solution of diisopropylamine (1. 08 mL, 7. 74 mmol) and TMEDA (2. 54 mL, 16. 89 mmol) in THF (15 mL, freshly distilled) at 0 C was added 1. 6 M n-BuLi (5. 27 mL, 8. 44 mmol) via a syringe. The solution was stirred for 30 min at 0 OC and was then cooled to-78 C, and a solution of 4-bromobenzo[b]thiophene (1. 5 g, 7. 03
mmol) in THF (7 mL) was added via a cannula. After stirring for 30 min, a solution of TMSC1 (1.07 mL, 8.44 mmol) in THF (8 mL) was added via a cannula. The solution was stirred overnight, while allowed to warm to room temperature. The solution was then concentrated under reduced pressure. Saturated aqueous NaHCO3 (100 mL) was added and the mixture was extracted with CH2C12 (4 x 80 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography [100% hexanes]. The purified fractions were combined and concentrated under reduced pressure to give (4-bromobenzo[b]thiophen-2-yl) trimethylsilane as a clear oil (1.7458 g, 87%). IR (KBr) 2959,972, 853, 838 cm-l. EI MS 286.2 (M + H) +, 271.1 (M-CH3) + EXAMPLE 14
(+/-)-3- (JV,. M-Dimethylamino) methyl-2- (2-trimethyl silylbenzo[b]thiophen-4-yl) bicyclo[2. 2. 1] heptan-2-ol Into a stirred solution of diisopropylamine (0.493 mL, 3.52 mmol) and TMEDA (1.16 mL, 7.689 mmol) in THF (6.5 mL, freshly distilled) at-78 Oc was added 1.6 M n-BuLi (2.40 mL, 3.84 mmol) via a syringe. The solution was warmed to 0 C for 20 min and re-cooled to-78 OC. A
solution of 4-bromobenzo [b] thiophene (0. 6828 g, 3. 204 mmol) in THF (3. 25 mL) was added via a cannula. After stirring for 20 min, a solution of TMSCl (0. 488 mL, 3. 84 mmol) in THF (3.25 mL) was added via a cannula. The solution was stirred overnight, while allowed to warm to room temperature. Saturated aqueous NH4Cl (10 mL) was added and the mixture was extracted with Et20 (3 x 15 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure to give 4-bromo-2-trimethylsilylbenzo [b] thiophene as a gold oil (0.845 g, 92%).
Into a solution of crude 4-bromo-2 trimethylsilylbenzo [b] thiophene (0.500 g, 1.75 mmol) and TMEDA (1.32 mL, 8.76 mmol) in THF (5 mL) cooled at-78 Oc was added 1.6 M n-BuLi (1.20 mL, 1.927 mmol) via a syringe. After stirring for 30 min, a solution of (+/ )-3- (N, N-dimethylamino) methylbicyclo [2. 2. 1] heptan-2-one, (0.293 g, 1.75 mmol) in THF (2 mL) was added via a cannula. After stirring overnight, the solution was diluted with H2O (25 mL) and saturated aqueous NH4Cl (25 mL). The mixture was extracted with EtOAc (3 x 50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was then purified by silica gel chromatography (2% (2.0 M NH3 in MeOH)/CH2Cl2). The purified fractions were concentrated
under reduced pressure and placed under vacuum to give the title compound as a yellow oil. (0. 3351 g, 51%). IR (KBr) 3005,2959, 1251,993, 842 cm-l. Ion Spray MS 374.2 (M +H) +.
EXAMPLE 15 (+/-)-((3-(Benzo[b]thiophen-4-yl)bicyclo[2. 2. 1]-hept-2- en-2-yl) methyl) dimethylamine
Into a solution of (+/-)-3- (N, N-dimethylamino) methyl-2 (2-trimethylsilylbenzo [b] thiophen-4-yl) bicyclo [2. 2. 1] heptan-2-ol, (0. 2958 g, 0. 791 mmol) in CH2C12 (7. 9 mL) cooled at 0 C was added TFA (3.1 mL), while stirring.
After 2 h, TBAF (1. 58 mil, 1.58 mmol, 1.0 M in THF) was added via an addition funnel. The mixture was stirred for 3 h, and then concentrated under reduced pressure.
The oily residue was diluted with saturated aqueous NaHCO3 (50 mL) and extracted with CH2Cl2 (3 x 50 mL).
The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (3% (2.0 M NH3 in MeOH)/CH2Cl2). The purified fractions were concentrated under reduced pressure and placed under vacuum. The title compound turned to a white solid upon standing (0.2095 g, 93%). mp 73.5-76. 9 oc. IR (KBr)
2950, 2870, 2820, 2777, 1454 em-i. Ion Spray MS 284. 1 (M + H) + ; 239.0 (M-N (CH3) 2)-.
Similarly prepared were:
(+/-)- ( (3- (Benzo [b] thiophen-7-yl) bicyclo [2. 2. 1]-hept-2en-2-yl) methyl) dimethylamine, mp 79. 6-80. 5 OC. IR (KBr) 2949, 2870, 2820, 2777, 1456 cm-1. Ion Spray MS 284. 1 (M + H) + ; 239. 0 (M-N (CH3) 2) + (+/-)-Dimethyl ( (3- (2-methylbenzo[b]thiophen-5yl) bicyclo [2. 2. 1]-hept-2-en-2-yl) methyl) amine, IR (KBr) 2962, 2950, 2921, 2870, 2819, 2775, 1446 cm-1. FD+ MS 297.3 (M) + EXAMPLE 16 (+/-) -Dimethyl ((3-(2-methylbenzo[b]thiophen-5- yl) bicyclo [2. 2. 1]-hept-2-en-2-yl) methyl) amine hydrochloride Into a solution of (+/-)-dimethyl ( (3- (2-methylbenzo [b] thiophen-5-yl) bicyclo [2. 2. 1]-hept-2-en-2-
yl) methyl) amine, (0. 26740 g, 0. 898 mmol) in MeOH (1 mL) was added HCl (0.90 mL, 0.898 mmol, 1.0 M in Et2O), while stirring. The mixture was stirred for 10 min, diluted with H20 (20 mL), and lyophilized to afford an
off-white powder, (0. 2953 g, 98%). mp 206. 5-214. 2 OC.
Ion Spray MS 298. 1 (M + H) ; 253. 0 (M-N (cl3) 2) Similarly prepared were : N, N-dimethyl [3- (2-methyl-l-benzothien-4yl) bicyclo [2. 2. 1] hept-2-en-2-yl] methanamine hydrochloride, mp 181. 6-189. 1 OC. IR (KBr) 2967, 1473 cm-l. Ion Spray MS 298. 1 (M + H) + ; 253. 0 (M-N (cl3) 2) + N, N-dimethyl [ (lR, 4S)-3- (2-methyl-l-benzothien-6yl) bicyclo [2. 2. 1] hept-2-en-2-yl] methanamine hydrochloride, mp 68. 2 Oc (dec.). Ion Spray MS 298. 3 (M + H) + ; 253. 2 (M-N (CH3) 2) N, N-dimethyl [3- (2-methyl-l-benzothien-7yl) bicyclo [2. 2. 1] hept-2-en-2-yl] methanamine hydrochloride, mp 179. 5-181. 6 oC. Ion Spray MS 298. 3 (M + H) + ; 253. 2 (M-N (CH3) z) [3- (2-fluoro-l-benzothien-5-yl) bicyclo [2. 2. 1] hept-2-en2-yl]-N, N-dimethylmethanamine, maleic acid, mp 168. 1168. 82C
[3- (3-chloro-l-benzothien-5-yl) bicyclo [2. 2. 1] hept-2-en2-yl]-N, N-dimethylmethanamine hydrochloride, mp 223-226 C N, N-dimethyl [3- (3-methyl-l-benzothien-5yl) bicyclo [2. 2. 1] hept-2-en-2-yl] methanamine hydrochloride, FIA POS MS (M+H, 298. 1) N, N-dimethyl [3- (3-methyl-l-benzothien-7yl) bicyclo [2. 2. 1] hept-2-en-2-yl] methanamine hydrochloride, mp 236-2392C N, N-dimethyl [3- (3-methyl-l-benzothien-6yl) bicyclo [2. 2. 1] hept-2-en-2-yl] methanamine hydrochloride, mp 131-1342C N, N-dimethyl [3- (3-methyl-l-benzothien-4yl) bicyclo [2. 2. 1] hept-2-en-2-yl] methanamine hydrochloride, mp 2252C [ (lR, 4S)-3- (l-benzothien-5-yl) bicyclo [2. 2. 1] hept-2-en-2yl]-N, N-dimethylmethanamine hydrochloride, mp 236. 4236. 72C [ (lS, 4R)-3- (l-benzothien-5-yl) bicyclo [2. 2. 1] hept-2-en-2yl]-N, N-dimethylmethanamine hydrochloride, mp 236. 4236. 62C
EXAMPLE 17 (+/-)-3- (N-Dimethylamino) methylbicyclo [3. 2. 1] octan-2 one Into a slurry of bicyclo [3. 2. 1] octan-2-one (1.50 g, 12.07 mmol), dimethylamine hydrochloride (1.28 g, 15.70 mmol), and paraformaldehyde (0.478 g, 5.31 mmol) in EtOH (15 mL) was added concentrated HCl (0.4 mL), while stirring. The mixture was stirred at reflux for 3 days and concentrated under reduced pressure. Upon standing, crystals formed. The crystals were suspended in Et20 (10 mL) and acetone (1 mL) for 15 min. The crystals were
filtered and washed with Et20. The crystals were then dissolved in saturated aqueous Nah03 (50 mL), forming the free base, and extracted with Et20 (3 x 50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. After being placed under vacuum, the title compound was obtained as a yellow oil, (1.1963 g, 54%). IR (KBr) 2947,1703 cm-l.
Ion Spray MS 182.1 (M + H) +.
EXAMPLE 18 3-{[allyl (methyl) amino]methyl}-bicyclo[3. 2. 1]octan-2-one
Bicyclo [3. 2. 1] octan-2-one (1. 24 g, 10 mmol) was place in a 50 mL round bottomed flask equipped with a stirrer bar. A solution of dimethyl amine (10 mL, 20 mmol, 2.0 M solution in MeOH) was added followed by 40% aqueous formaldehyde solution (1.5 mL, 20mmol) and c HCl (1 mL).
The resulting solution was heated with stirring at 70 C overnight. After cooling to room temperature the solvents were evaporated in vacuo. The residue was then partitioned between EtOAc and saturated aqueous Na2CO3 and the layers separated. The organic extract was washed with brine and dried over anh. MgS04, filtered and the
solvent evaporated to give a brown oil (1. 70 g, 9. 4 mmol), FIA [M+l] =182. 1. This oil was then taken up in MeOH (15 mL) and MeI (5 mL) added. Resulting solution was stirred at room temperature overnight. The solvents were evaporated in vacuo and the resulting residue taken up in DCM (25 mL) and 5% aqueous NaHCO3 (25 mL) added. This solution was stirred at room temperature overnight. Layers separated and aqueous extract reextracted with DCM. Organic extracts combined, dried over anh. MgS04, filtered and the solvent evaporated in
vacuo to give a gum (1. 07 g, 8. 8 mmol). This gum was taken up in MeOH (10 mL) and N-methylallyl amine (910 p. L, 9. 5 mmol) added and stirred at room temperature
overnight. The solvent was evaporated to give the desired product as a yellow oil (1. 12 g, 5. 4mmol). Mass spec. positive FIA [M+H] =208. 1.
EXAMPLE 19
3- (l-pyrrolidinylmethyl) bicyclo [3. 2. 1] octan-2-one 3- (N, N-Dimethylamino) methylbicyclo [3. 2. 1] octan-2-one (2. 0 g, 11 mmol) was taken up in MeOH (18 mL) and methyl iodide (6 mL) added with stirring. The reaction was stirred at room temperature overnight. Solvents evaporated and the residue re-suspended in DCM (30 mL) and 5% aqueous Nah03 (30 mL) was added. The resulting solution was stirred at room temperature overnight.
Layers separated and aqueous extract re-extracted with DCM. Organic extracts combined, dried over anh. MgSO4, filtered and the solvent evaporated in vacuo to give a brown oil (1.38 g, 10. lmmol). ). This oil taken up in MeOH (10 mL) and pyrrolidine (763gel, 9.1 mmol) added.
The resulting solution was stirred at room temperature overnight and the solvents evaporated in vacuo to the desired product as an oil (1.91 g, 9.22 mmol). Mass spec. positive FIA [M+H] =208. 1.
Similarly prepared was:
3- (l-azetidinylmethyl) bicyclo [3. 2. 1] octan-2-one, Mass spec. positive FIA [M+H] =193. 1.
EXAMPLE 20 (+/-)-3- (N, N-Dimethylamino) methyl-2- (5 fluorobenzo[b]thiophen-2-yl) bicyclo[3. 2. 1] octan-2-ol Into a stirred solution of 5-fluorobenzo[b]thiophene (0.209 mL, 1.379 mmol) and TMEDA (1.04 mL, 6.89 mmol) in
THF (4 mL, freshly distilled) at-78 Oc was added 1. 6 M n-BuLi (0.95 mL, 1.51 mmol) via a syringe. After stirring for 40 min, a solution of (+/-)-3- (N, Ndimethylamino) methylbicyclo [3. 2. 1] octan-2-one (0.250 g, 1.379 mmol) in THF (2 mL) was added via a cannula. The solution was stirred overnight, while allowed to warm to room temperature, and concentrated under reduced pressure. The residue was diluted with saturated
aqueous Nah03 (50 mL). The mixture was extracted with CH2C12 (3 x 40 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was then purified by silica gel chromatography (3. 5% (2. 0 M NH3 in MeOH)/CH2C12). The purified fractions were concentrated under reduced pressure and placed under vacuum,
resulting in the title compound, (+/-)-3- (N, Ndimethylamino) methyl-2- (5-fluorobenzo[b]thiophen-2yl) bicyclo [3. 2. 1] octan-2-ol as a white foam (0. 2912 g, 63%). IR (KBr) 3004, 2952, 2863, 2831, 2787, 1443 cm-l.
Ion Spray MS 334. 0 (M + H) +. similarly prepared was : allyl (methyl) amino] methyl}-2- [3-methyl-2 (trimethylsilyl)-l-benzothien-5-yl] bicyclo [3. 2. 1] octan2-ol, Mass spec. positive FIA [M+H] =440.
EXAMPLE 21 3- [ (dimethylamino) methyl]-2- (6-fluoro-2-naphthyl) bicyclo [3. 2. 1] octan-2-ol The enantiomers of 3-[ (dimethylamino) methyl]-2- (6fluoro-2-naphthyl) bicyclo [3. 2. 1] octan-2-ol were separated by chiral preparative chromatography, using a CHIRALPAK-AD colunm, and a mixture of Hexane/Ethanol 50/50. as the eluant, FIA Pos MS (M+H, 328. 1).
EXAMPLE 22 (+/-)-dimethyl ( (2- (5-fluorobenzo[b]thiophen-2yl) bicyclo [3. 2. 1]-oct-2-en-3-yl) methyl) amine hydrochloride
Into a solution of (+/-)-3- (N, N-dimethylamino) methyl-2 (5-fluorobenzo[b]thiophen-2-yl) bicyclo[3. 2. 1] octan-2 ol, (0.212 g, 0.637 mmol) in CH2C12 (7 mL) cooled at 0 C was added TFA (2.5 mL), while stirring. The mixture was stirred for 3 days, and diluted with saturated aqueous NaHCO3 (50 mL). The mixture was extracted with CH2C12 (3 x 50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure.
The residue was purified by silica gel chromatography (4% (2.0 M NH3 in MeOH)/CH2Cl2). The purified fractions were concentrated under reduced pressure and placed under vacuum, resulting in (+/-)-Dimethyl ( (2- (5 fluorobenzo[b]thiophen-2-yl) bicyclo[3. 2. 1]-oct-2-en-3- yl) methyl) amine as a yellow oil, (0.1697 g, 84%). IR
(KBr) 2943, 2864, 2824, 1604, 1444 cm-Ion Spray MS 316.1 (M + H) + ; 271.1 (M-N (CH3) 2)".
Into a solution of (+/-)-dimethyl ( (2- (5 fluorobenzo[b]thiophen-2-yl) bicyclo[3. 2. 1]-oct-2-en-3yl) methyl) amine, (0.1346 g, 0.426 mmol) in MeOH (1 mL) was added HC1 (0.42 mL, 0.426 mmol, 1.0 M in Et20), while stirring. The mixture was stirred for 10 min and diluted with H2O (15 mL) and just enough CH3CN to dissolve the salt (1 mL). The mixture was then lyophilized to afford a white powder, (0.1487 g, 99%).
mp 197. 9-203. 8 C. Ion Spray MS 316. 3 (M + H) + ; 271. 2 (M - N (CH3) 2)'.
Similarly prepared were : N, N-dimethyl [2- (2-naphthyl) bicyclo [3. 2. 1] oct-2-en-3yllmethanamine, maleic acid, mp 164-1662C N, N-dimethyl [2- (6-fluoro-2-naphthyl) bicyclo [3. 2. 1] oct2-en-3-yl] methanamine, maleic acid, mp 172-1742C N, N-dimethyl [ (lS, 5R)-2- (6-fluoro-2-naphthyl) bicyclo [3. 2. 1] oct-2-en-3-yl] methanamine, maleate, FIA Pos mass spec, (M+H 310. 2) N, N-dimethyl [ (lR, 5S)-2- (6-fluoro-2-naphthyl) bicyclo [3. 2. 1] oct-2-en-3-yl] methanamine, maleate, FIA Pos mass spec, (M+H 310. 2/311. 1) [2- (7-fluoro-l-benzothien-2-yl) bicyclo [3. 2. 1] oct-2-en3-yl]-N, N-dimethylmethanamine hydrochloride, mp 210. 3214. 7 C. Ion Spray MS 316. 3 (M + H) + ; 271. 1 (M N (CH3) 2)
[2- (4-fluoro-l-benzothien-2-yl) bicyclo [3. 2. 1] oct-2-en-3yl]-N, N-dimethylmethanamine hydrochloride, mp 216. 1 218.4 OC. Ion Spray MS 316.0 (M + H) + [2-(6-fluoro-1-benzothien-2-yl)bicyclo[3. 2. 1] oct-2-en-3- yl]-N, N-dimethylmethanamine hydrochloride, mp 207.4211. 1 C. Ion Spray MS 316.0 (M + H) + ; 270.9 (M N (CH3) 2) [ (lS, 5R)-2- (6-fluoro-l-benzothien-2-yl) bicyclo [3. 2. 1] oct-2-en-3-yl]-N, N-dimethylmethanamine hydrochloride, LC-MS (M+H, 316.1, 98.1%) [(1R,5S)-2-(6-fluoro-1-benzothien-2-yl) bicyclo [3. 2. 1] oct-2-en-3-yl]-N, N-dimethylmethanamine hydrochloride, FIA POS MS (M+H, 316.1) [2-(6-fluoro-1-benzothien-3-yl)bicyclo[3. 2. 1] oct-2-en-3- yl]-N, N-dimethylmethanamine hydrochloride, FIA POS MS (M+H, 316.2)
2- {3- [ (dimethylamino) methyl] bicyclo [3. 2. 1] oct-2-en-2yl}-l-benzothiophene-6-carbonitrile hydrochloride, FIA POS MS (M+H, 323)
[2- (6-trifluoro-l-benzothien-3-yl) bicyclo [3. 2. 1] oct-2en-3-yl]-N, N-dimethylmethanamine hydrochloride, mp 1551582C N, N-dimethyl [3- (2-naphthyl) bicyclo [2. 2. 2] oct-2-en-2yllmethanamine, maleate, mp 205 Oc [3- (6-methoxy-2-naphthyl) bicyclo [2. 2. 2] oct-2-en-2-yl] N, N-dimethylmethanamine, maleate, mp 177 2C [3- (1-benzothien-3-yl) bicyclo [2. 2. 2] oct-2-en-2-yl]-N, Ndimethylmethanamine, maleate, mp 1812C 6- {3-[ (dimethylamino) methyl]bicyclo[2. 2. 2] oct-2-en-2yl}-2-naphthol, maleate, mp 1962C [3- (6-fluoro-2-naphthyl) bicyclo [2. 2. 2] oct-2-en-2-yl] N, N-dimethylmethanamine, maleate, mp 198il [3- (6-fluoro-l-benzothien-3-yl) bicyclo [2. 2. 2] oct-2-en-2yl]-N, N-dimethylmethanamine hydrochloride, FIA POS MS (M+H, 316. 1)
l- { [3- (l-benzothien-5-yl) bicyclo [3. 2. 1] oct-2-en-2 yl] methyl} pyrrolidine hydrochloride, LC-MS pos m/z (M+H, 324,100%), mp 135-138 C 1-{[3-(1-benzothien-5-yl)bicyclo[3. 2. 1]oct-2-en-2yl]methyl}azetidine hydrochloride, LC-MS pos m/z (M+H, 310,100%), mp 97-992C 1-{[3-(3-methyl-1-benzothien-5-yl)bicyclo[2. 2. 2] oct-2- en-2-yl] methyl} pyrrolidine hydrochloride, FIA POS MS (M+H, 338.6) [3- (1-benzothien-7-yl) bicyclo [2. 2. 2] oct-2-en-2-yl]-N- methylmethanamine hydrochloride, FIA POS MS (M+H, 284.1) EXAMPLE 23 (+/-)-dimethyl[3-(methyl-1-benzothien-5yl]bicyclo[3. 2. 1] octan-2-ol
3-methyl-2- [3-methyl-2- (trimethylsilyl)-l-benzothien-5yl] bicyclo [3. 2. 1] octan-2-ol (2. 47 g, 6. 2 mmol) was taken up in THF (20 mL) with stirring. A solution of TBAF (6.2 mL, 1M solution in THF with 5 wt. % water ex. Aldrich) was added and the resulting solution stirred at room temperature for 3 h. The solvents were evaporated and
the residue taken up in ethyl acetate and washed with 5% NaHCO3 solution and brine. After drying over MgSO4 the solvent was removed in vacuuo to give an oil which was purified by column chromatography (hex: EtOAc, 8: 2). Gave the desired product as an oil (1.12 g, 3.2 mmol). Mass spec. positive FIA [M+H] =330. 2.
EXAMPLE 24 [2- (l-Benzothien-5-yl) bicyclo [3. 2. 1]oct-2-en-3-yl]-N, Ndimethylmethanamine hydrochloride
[2- (l-benzothien-5-yl)-3- [ (dimethylamino) methyl] bicyclo [3. 2. 1] octan-2-ol (1. 0 g, 3. 1 mmol) was treated with p-toluene sulfonic acid (2.67 g, 15 mmol, 5 equiv) in DCM (30 mL). The reaction was heated at reflux overnight. DCM was removed in vacuo and the residue taken up in ethyl acetate and washed successively with 1M NaOH solution (x5), brine, dried over anh. MgSO4 and concentrated in vacuo to give an oil (880 mg, 2.83 mmol), Ion Spray MS 298.2 (M + H) ; 253.1 (M-N (CH3) 2)'' Into a solution of [2- (l-benzothien-5-yl) bicyclo [3. 2. 1] oct-2-en-3-yl]-N, N-dimethylmethanamine (880 mg, 2.83 mmol) in MeOH (1 mL) was added HCl (0.29 mL, 2.83 mmol, 1.0 M in Et20), while stirring. The mixture was stirred for 10 min and diluted with H2O (15 mL) and just enough CH3CN to dissolve the salt (1 mL). The mixture was then lyophilized to afford a white powder, [2-d-benzothien-
5-yl) bicyclo [3. 2. 1] oct-2-en-3-yl]-N, Ndimethylmethanamine hydrochloride, mp 57. 8 OC.
Similarly prepared was : N-allyl-N-methyl-N- { [2- (3-methyl-l-benzothien-5yl) bicyclo [3. 2. 1]oct-2-en-3-yl]methyl} amine, Mass spec. positive FIA [M+H] =338. 3.
[ (lR, 5S)-2- (l-benzothien-5-yl) bicyclo [3. 2. 1] oct-2-en-3yl]-N, N-dimethylmethanamine hydrochloride, mp 225. 3225. 62C [ (lS, 5R)-2- (l-benzothien-5-yl) bicyclo [3. 2. 1] oct-2-en-3yl]-N, N-dimethylmethanamine hydrochloride, mp 225. 6226. 02C [2- (1-benzothien-6-yl) bicyclo [3. 2. 1] oct-2-en-3-yl]-N, Ndimethylmethanamine hydrochloride, mp 81. 5 OC. Ion Spray MS 298. 1 (M + H) ; 253. 0 (M-N (CH3) 2) + [2- (l-benzothien-4-yl) bicyclo [3. 2. 1] oct-2-en-3-yl]-N, Ndimethylmethanamine hydrochloride, mp 182. 4 C. Ion Spray MS 298. 2 (M + H) ; 253. 1 (M-N (CH3) 2) +
[ (lS, 5R)-2- (l-benzothien-4-yl) bicyclo [3. 2. 1] oct-2-en-3yl]-N, N-dimethylmethanamine hydrochloride, LC-MS (M+H, 298. 1, 100%) [ (lR, 5S)-2- (l-benzothien-4-yl) bicyclo [3. 2. 1] oct-2-en-3yl]-N, N-dimethylmethanamine hydrochloride, LC-MS (M+H, 298. 1, 100%) [2- (l-benzothien-7-yl) bicyclo [3. 2. 1] oct-2-en-3-yl]-N, Ndimethylmethanamine hydrochloride, mp 205. 0 C (dec.).
Ion Spray MS 298. 1 (M + H) + ; 253. 1 (M-N (CH3) 2) + [ (lS, 5R)-2- (l-benzothien-7-yl) bicyclo [3. 2. 1] oct-2-en-3yl]-N, N-dimethylmethanamine hydrochloride, mp 244-2452C I [ (lR, 5S)-2- (l-benzothien-7-yl) bicyclo [3. 2. 1] oct-2-en-3yl]-N, N-dimethylmethanamine hydrochloride, mp 245-2462C [2- (3-chloro-l-benzothien-5-yl) bicyclo [3. 2. 1] oct-2-en-3yl]-N, N-dimethylmethanamine hydrochloride, mp 233-2352C N, N-dimethyl [-2- (3-methyl-l-benzothien-5yl) bicyclo [3. 2. 1] oct-2-en-3-yl] methanamine hydrochloride, FIA POS MS (M+H, 312. 1)
N, N-dimethyl [ (lS, 5R)-2- (3-methyl-l-benzothien-5yl) bicyclo [3. 2. 1] oct-2-en-3-yl] methanamine hydrochloride, FIA POS MS (M+H, 312.1) N, N-dimethyl [ (lR, 5S)-2- (3-methyl-l-benzothien-5- yl) bicyclo [3. 2. 1] oct-2-en-3-yl] methanamine hydrochloride, FIA POS MS (M+H, 312.1) N, N-dimethyl[2-(3-methyl-1-benzothien-7-yl) bicyclo [3. 2. 1] oct-2-en-3-yl] methanamine hydrochloride,
[3- (1-benzothien-5-yl) bicyclo [2. 2. 2] oct-2-en-2-yl]-N, Ndimethylmethanamine hydrochloride, mp 209. 7-210. 02C [3- (l-benzothien-6-yl) bicyclo [2. 2. 2] oct-2-en-2-yl]-N, Ndimethylmethanamine hydrochloride, mp 206. 4-206. 92C [3- (3-chloro-l-benzothien-5-yl) bicyclo [2. 2. 2] oct-2-en-2 yl]-N, N-dimethylmethanamine hydrochloride, mp 224.6225. 92C N, N-dimethyl[3-(3-methyl-1-benzothien-5-yl) bicyclo [2. 2. 2] oct-2-en-2-yl] methanamine hydrochloride, FIA POS MS (M+H, 312.1)
[3- (1-benzothien-7-yl) bicyclo [2. 2. 2] oct-2-en-2-yl]-N, Ndimethylmethanamine hydrochloride, mp 254-2562C [3- (l-benzothien-4-yl) bicyclo [2. 2. 2] oct-2-en-2-yl]-N, Ndimethylmethanamine hydrochloride, mp 207. 8-209. 9 sc
EXAMPLE 25 N-Methyl-N- { [2- (3-methyl-l-benzothien-5yl) bicyclo [3. 2. 1] oct-2-en-3-yl] methyl} amine, hydrochloride salt, N-allyl-N-methyl-N- {[2- (3-methyl-l-benzothien-5yl) bicyclo [3. 2. 1] oct-2-en-3-yl] methyl} amine (880 mg, 2. 61 mmol) was taken up in dry, degassed DCM (10 mL) under N2 atmosphere. This solution was transferred via a cannular into a second flask containing Pd (PPh3) 4 (59 mg, 0.052 mmol) and 1, 3-dimethylbarbituric acid (1.22 g, 7.83 mmol). The resulting solution was stirred at 40 Oc for 5 h. Reaction cooled to room temperature and diluted with DCM. The resulting solution was washed with saturated Na2CO3 solution (x5), dried over anh. MgSO4 and concentrated in vacuo to give an oil which was purified by column chromatography (MeOH: DCM, 1: 9 an 1% of 2M NH3/MeOH solution) to give a gum (360 mg, 1.21 mmol).
This was converted to the HC1 salt using 1. 0M solution
HC1 in ether to give the desired product as a white solid. MP=204. 5-206. 7 and mass spec. positive FIA [M+H] =298. 2 Similarly prepared was:
[3- (6-fluoro-2-naphthyl) bicyclo [3. 2. 1] oct-2-en-2-yl]-Nmethylmethanamine, hydrochloride salt, mp 200. 4-202. 8 C EXAMPLE 26 N, N-Dimethyl [3- (6- { [4- (trifluoromethyl) benzyl] oxy}-2 naphthyl) bicyclo [2. 2. 2] oct-2-en-2-yl] methanamine A 100ml round bottomed flask was charged with a 0. 06M solution of 7-f3- [ (dimethylamino) methyll- bicyclo [2. 2. 2] oct-2-en-2-yl}-2-naphthol (220mg, 0. 716mmol) in amine-free N, N-dimethylformamide (DMF, 11.92mls). To this solution was added a solution of sodium bis (trimethylsilyl) amide (1M in tetrahydrofuran, 1.073ml, 1. 073mmol, 1.5eq). The flask was flushed with nitrogen, stoppered and its contents stirred at r. t. for one hour, during which time the solution changed in colour from yellow to dark brown. Twenty alkyl and benzyl halides were each dissolved in amine-free DMF (550 l to 1000 l) such that in each case, a 0. 12M solution was made up. An aliquot of each (500 l, 0. 06mmol) was placed
in its own 4ml Reacti-Vial. To each Vial, under a blanket of nitrogen, was added an aliquot of the naphtholate solution prepared above (50OR1, 0. 03mmol).
The twenty Vials were sealed, and their contents stirred and heated to 80 C overnight. The Vials were then unsealed and in each case, the contents were treated with methanol (lml). Each mixture was passed through its own methanol-conditioned 500mg SCX ion-exchange cartridge (under gravity) into a collection tank. Each cartridge was then washed with fresh methanol (2x2.5ml) such that the washings also passed into the tank. A clear glass vial was then placed underneath each cartridge, which were then eluted with 2M ammonia in methanol to release the products. Solvents were removed in vacuo to recover the target materials. FIA POS MASS SPEC (M+H, 466 & [M-N (CH3) 2]+, 421).
Similarly prepared were: [3- (6-methoxy-2-naphthyl) bicyclo [2. 2. 2] oct-2-en-2-yl]- N, N-dimethylmethanamine, FIA POS MASS SPEC (M+H, 322 & [M-N (CH3) 2 : T, 277)
[3- (6-butoxy-2-naphthyl) bicyclo [2. 2. 2] oct-2-en-2-yl] N, N-dimethylmethanamine, FIA POS MASS SPEC (M+H, 364 & [M-N (CH3) 2] 319)
{3- [6- (benzyloxy)-2-naphthyl] bicyclo [2. 2. 2] oct-2-en-2yl}-N, N-dimethylmethanamine, FIA POS MASS SPEC (M+H, 398 & [M-N (CH3) 2] 353) (3-{6-[(4-bromobenzyl)oxy]-2-naphthyl}bicyclo[2. 2. 2] oct- 2-en-2-yl) -N, N-dimethylmethanamine, FIA POS MASS SPEC (M+H, 475/477 & [M-N (CH3) 21+, 430/432) 4-{[(6-{3-[(dimethylamino)methyl]bicyclo[2. 2. 2] oct-2-en- 2-yl} -2-naphthyl) oxy] methyl} benzonitrile, FIA POS MASS SPEC (M+H, 423 & [M-N (CH3) 21+, 378) (3-{6-[(3-chlorobenzyl)oxy]-2-naphthyl}bicyclo[2. 2. 2] oct-2-en-2-yl) -N, N-dimethylmethanamine, FIA POS MASS SPEC (M+H, 432 & [M-N (CH3) 2T, 387)
N, N-dimethyl (3- {6- [ (4-methylbenzyl) oxy]-2naphthyl} bicyclo [2. 2. 2] oct-2-en-2-yl) methanamine, FIA POS MASS SPEC (M+H, 412 & [M-N (CH3) 2, 367) (3- {6- [ (2, 6-dichlorobenzyl) oxy]-2-naphthyl} bicyclo [2. 2. 2] oct-2-en-2-yl)-N, N-dimethylmethanamine, FIA POS MASS SPEC (M+H, 466/468 & [M-N (CH3) 2]+, 421/423)
[3- (6-ethoxy-2-naphthyl) bicyclo [2. 2. 2] oct-2-en-2-yl] N, N-dimethylmethanamine, FIA POS MASS SPEC (M+H, 336 & [M-N (CH3) 2] 291) (3- {6- [ (4-tert-butylbenzyl) oxy]-2-naphthyl} bicyclo [2. 2. 2] oct-2-en-2-yl)-N, N-dimethylmethanamine, FIA POS MASS SPEC (M+H, 454 & [M-N (CH3) 21+, 409) (3-{6-[(2-chlorobenzyl)oxy]-2-naphthyl} bicyclo [2. 2. 2] oct-2-en-2-yl)-N, N-dimethylmethanamine, FIA POS MASS SPEC (M+H, 432 & [M-N (CH3) 2]+, 387) (3-{6-[(4-fluorobenzyl)oxy]-2-naphthyl} bicyclo [2. 2. 2] oct-2-en-2-yl)-N, N-dimethylmethanamine, FIA POS MASS SPEC (M+H, 416 & [M-N (CH3) 2] , 371) N, N-dimethyl[3-(6-propoxy-2-naphthyl)bicyclo[2. 2. 2] oct- 2-en-2-yl] methanamine, FIA POS MASS SPEC (M+H, 350 & [M N (CH3) 2]+, 305) 3-{6-[(4-methoxybenzyl)oxy]-2-naphthyl} bicyclo [2. 2. 2] oct-2-en-2-yl)-N, N-dimethylmethanamine, FIA POS MASS SPEC (M+H, 428 & [M-N (CH3) 2] , 383)
N, N-dimethyl (3- {6- [ (4-nitrobenzyl) oxy]-2naphthyl} bicyclo [2. 2. 2] oct-2-en-2-yl) methanamine, FIA POS MASS SPEC (M+H, 443 & [M-N (CH3) 2, 398) N, N-dimethyl[3- (6- {[4- (trifluoromethoxy) benzyl]oxy}-2 naphthyl) bicyclo [2. 2. 2] oct-2-en-2-yl] methanamine, FIA POS MASS SPEC (M+H, 482 & [M-N (CH3) 2, 437) EXAMPLE 27 Tablets each containing 10 mg of active ingredient are made up as follows: Active ingredient 10 mg Starch 160 mg Microcrystalline cellulose 100 mg Polyvinylpyrrolidone (as 10% solution in water) 13 mg Sodium carboxymethyl starch 14 mg Magnesium stearate 3 mg Total 300 mg The active ingredient, starch and cellulose are mixed thoroughly. The solution of polyvinylpyrrolidone is
mixed with the resultant powders and passed through a sieve. The granules so produced are dried and re-passed through a sieve. The sodium carboxymethyl starch and magnesium stearate are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 300 mg.
EXAMPLE 28 Capsules each containing 20 mg of medicament are made as follows: Active ingredient 20 mg Dried starch 178 mg Magnesium stearate 2 mg Total 200 mg The active ingredient, starch and magnesium stearate are passed through a sieve and filled into hard gelatine capsules in 200 mg quantities.
EXAMPLE 29 [3H]-Citalopram Binding Assay
The ability of compounds of the invention to displace [3H]-citalopram from binding sites on rat cerebral cortical membranes was measured in the following way: In each well of a 96 deep well plate was added: 100ml 2nM [3H]-citalopram
600ml 50mM Tris. HCl pH 7. 4 containing 150mM NaCl and 5mM KC1 100ml Diluted compound, 50mM Tris. HCl pH 7. 4 containing 150mM NaCl and 5mM KC1 (total binding) or lOOmM fluoxetine (non-specific binding) 200ml Membrane preparation (0. 75mg protein per ml) The microtitre plates were incubated at 370C for 90minutes followed by filtration through GF/B filters soaked in 50mM Tris. HC1/0. 1% (w/v) polyethylenimine
pH 7. 4. The filter was washed 5 times with 50mM Tris. HC1. pH 7. 4. The filters were removed, dried and the bound tritium determined by liquid scintillation spectrometry. The results were analysed using an automatic spline fitting programme to provide Ki values for each of the compounds.

Claims (9)

  1. CLAIMS 1. A compound of the formula
    in which Rl and R2 are each hydrogen or Cl-4 alkyl, or Rl and R2 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholino group, said group being optionally substituted with 1 to 3 substituents selected from Cl-4 alkyl, hydroxymethyl, Cl-4 alkoxymethyl and amido, R3 is a naphthyl, indolyl, benzothienyl, benzofuranyl, benzothiazolyl, quinolinyl or isoquinolinyl group, said group being optionally substituted, and n is 1 or 2 and m is 0 or 1, provided that when m is 1 then n is 1; or a salt or ester thereof.
  2. 2. A compound according to Claim 1, in which Rl and R2 are each hydrogen or Cl-4 alkyl.
  3. 3. A compound according to either of Claims 1 and 2, in which R3 is optionally substituted 2-, 3-, 4-, 5-, 6-or 7-benzothienyl.
  4. 4. A compound according to Claims 3, in which R3 is optionally substituted 4-, 5- or 7-benzothienyl.
  5. 5. A compound according to Claim 1, of the formula
    in which Ri and R2 are each hydrogen or Cl-4 alkyl, R6 and R7 are each Cl-4 alkyl, Cl-4 alkoxy, carboxy,
    hydroxy, cyano, halo, trifluoromethyl,-NR'R'', - CONR'R'',-S02NR'R''or-SO2Rl where R'and R''are each hydrogen or Cl-4 alkyl, and p and q are each 0, 1 or 2; or a salt thereof.
  6. 6. A pharmaceutical formulation comprising a compound according to any of Claims 1 to 5, or pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable diluent or carrier therefor.
  7. 7. A compound according to any of Claims 1 to 5, or a pharmaceutically acceptable salt or ester thereof, for use as a pharmaceutical.
  8. 8. The use of a compound according to any of Claims 1 to 5, or a pharmaceutically acceptable salt or ester thereof; for the manufacture of a medicament for treating a disorder of the central nervous system.
  9. 9. A method of treating an animal, including a human, suffering or susceptible to a disorder of the central nervous system, which comprises administering a compound according to Claim 1, or a pharmaceutically acceptable salt or ester thereof.
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