Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1994-12-15
2001-08-07
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06271395
ABSTRACT:
OBJECT OF THE INVENTION
It is an object of the invention to provide the novel indanes of formula I and their non-toxic, pharmaceutically acceptable acid addition salts and a novel process and intermediates for their preparations.
It is another object of the invention to provide novel central analgesic compositions and a novel method of inducing central analgesic activity in warm-blooded animals.
These and other objects and advantages of the invention will become obvious from the following detailed description.
THE INVENTION
The novel compounds of the invention are selected from the group consisting of enantiomers and diastereoisomer forms and mixtures thereof of the formula
wherein R
6
is selected from the group consisting of hydrogen, halogen and alkyl and alkoxy of 1 to 5 carbon atoms, R
1
and R
2
are individually hydrogen or alkyl of 1 to 5 carbon atoms or taken together with the carbon atoms to which they are attached form a cycloalkyl of 3 to 6 carbon atoms optionally containing a heteroatom selected from the group consisting of —S—, —O— and —N—, one of A and B has the formula
and, the other has the formula
R is selected from the group consisting of hydrogen and alkyl of 1 to 5 carbon atoms, Z is selected from the group consisting of —(CH
2
)
n
—, branched alkylene of 2 to 8 carbon atoms and —CH
2
O—, n is an integer of 0 to 5, X, X′ and X″ are individually selected from the group consisting of hydrogen, alkyl and alkoxy of 1 to 4 carbon atoms, halogen, —OH, —CF
3
, —NO
2
, —NH
2
, mono and dialkylamino of 1 to 4 alkyl carbon atoms and sulfamino, R
3
and R
4
are individually selected from the group consisting of hydrogen and alkyl of 1 to 5 carbon atoms or taken together with the nitrogen atom to which they are attached form a 5 to 6 member heterocycle optionally containing a member of the group consisting of —O—, —S— and
R
1
′ is hydrogen or alkyl of 1 to 4 carbon atoms and their non-toxic, pharmaceutically acceptable acid addition salts.
When R
1
, R
2
, R
3
, R
4
, R
6
, R, X, X′ and X″ are alkyl, they are preferably methyl, ethyl, n-propyl or isopropyl but may also be n-butyl, isobutyl or n-pentyl. Examples of cycloalkyl formed by R
1
and R
2
and the carbon atoms to which they are attached are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of the cycloalkyl containing an oxygen, sulfur or nitrogen in the ring are tetrahydropyran, tetrahydrothiapyran and piperidinyl.
When Z is —(CH
2
)
n
—, n is preferably 0 or 1 and when Z is a branched alkylene, it is preferably alkylene substituted with methyl or ethyl such as 1,1-ethanediyl, methyl-1-ethanediyl-1,2, methyl-1 or -2-propanediyl-1,2 and ethyl-1-ethanediyl-1,2.
When R
6
, X, X′ and X″ are alkoxy, they are preferably methoxy or ethoxy but they may be other alkoxys such as propoxy, isopropoxy and linear and branched butoxy and when they are halogen, they are preferably chlorine but may be fluorine, iodine or bromine. When X, X′ and X″ are monoalkylamino or dialkylamino, the alkyls are preferably methyl or ethyl.
Examples of heterocycles formed by R
3
and R
4
and the nitrogen to which they are attached are pyridinyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, piperidinyl, morpholinyl and pyrrolidinyl.
Examples of suitable acids to form the non-toxic, pharmaceutically acceptable acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid and organic acids such as formic acid, acetic acid, propionic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, citric acid, oxalic acid, glyoxylic acid and aspartic acid, alkanesulfonic acids, such as methanesulfonic acid, arylsulfonic acids such as benzene sulfonic acid and arylcarboxylic acids such as benzoic acid.
Among the preferred compounds of formula I are those wherein A and B have the trans configuration, those wherein
has R
3
and R
4
both as methyl or together with the nitrogen form pyrrolidine, piperidine, or piperazine optionally substituted with alkyl of 1 to 3 carbon atoms, those in which
has R as hydrogen, methyl, or ethyl, Z is —CH
2
O—,
or —(CH
2
)
n
— and n is o or 1, those wherein R
1
and R
2
are both hydrogen or methyl or together with the carbon atoms form tetrahydropyran and those wherein X, X′ and X″ are individually selected from the group consisting of hydrogen, methyl, ethyl, methoxy, ethoxy, —NO
2
, sulfamino —CF
3
or chlorine and their non-toxic, pharmaceutically acceptable acid addition salts.
Examples of specific preferred compounds of formula I are
[trans (±)] 3,4-dichloro-N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-benzene-acetamide,
[trans (±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-3-nitro-benzene-acetamide,
[trans (±)] N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-4-nitro-benzene-acetamide,
[trans (±)] N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-(4-trifluoromethyl)-benzene-acetamide,
[trans (±)] 2-(3,4-dichlorophenoxy)-N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-acetamide,
[trans (±)] 3,4-dichloro-N-[2,3-dihydro-2-(dimethylamino)-1H-inden-1-yl]-N-methyl benzene acetamide,
[trans (±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-4-nitro-benzene-acetamide (isomer A), and their non-toxic, pharmaceutically acceptable acid addition salts.
The novel process of the invention for the preparation of the compounds of formula I wherein A and B have the trans configuration comprises reacting a compound of the formula
wherein R
6
, R
1
and R
2
have the above definition with a compound of the formula
wherein R has the above definition and R
5
is an amine protective group, preferably benzyl to obtain a compound of the formula
the hydroxy group is activated and reacted with an amine of the formula
wherein R
3
and R
4
have the above definitions to obtain a compound of the formula
removing the R
5
group to obtain a compound of the formula
reacting the latter with an acid or a functional derivative thereof of the formula
wherein Z, X, X′ and X″ have the above definitions to obtain a compound of formula I wherein A is
and R is
or the compound of formula II is reacted with an amine of the formula
to form a compound of the formula
activating the hydroxyl of the latter and reacting with an amine of the formula
NH
2
—R X
wherein R has the above definitions to obtain a compound of the formula
and reacting the latter with an acid of formula VIII or a functional derivative thereof to obtain a compound of formula I wherein A is
and B is
and optionally resolving the latter and/or forming the acid addition salts thereof.
Preferably, the hydroxyl functions of formulae IV and IX are activated with methanesulfonyl chloride and the protective group R
5
of formula VI is benzyl which can be removed by catalytic hydrogenation in the presence of a palladium catalyst. The activation of the hydroxyl of the compounds of formula VIII is effected in the presence of carbonyldiimidazole and the acids of formula VIII are used in the acid chloride or mixed anhydride form. The resolution of the compounds of formula I can be effected by known methods.
The process of the invention to form the compounds of formula I wherein A and B have the cis configuration may be prepared by the following reaction scheme:
The compounds with the formula (I) as defined above as well as their addition salts with acids show useful pharmacological properties. They show in particular a strong affinity for the opiate receptors and in particular for the K receptors and are endowed with central analgesic properties.
They are also endowed with diuretic properties and anti-arrythmic, anti-cerebral, ischaemic and hypotensive properties.
The novel central analgesic compositions of the invention are comprised o
Clemence Francois
Delevallee Francoise
Fortin Michel
Le Martret Odile
Bierman, Muserlian and Lucas
Hoechst Marion Roussol
McKane Joseph K.
Murray Joseph
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