Substituted tetracyclic tetrahydrofuran derivatives

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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C514S215000, C514S231500, C514S232800, C514S236800, C514S237200, C514S253030, C514S254080, C514S321000, C514S323000, C514S324000, C514S414000, C514S415000, C514S417000, C514S422000, C514S425000, C514S431000, C514S450000, C514S452000, C514S453000, C514S459000, C514S461000

Reexamination Certificate

active

06288058

ABSTRACT:

This invention concerns substituted tetracyclic tetrahydrofuran derivatives having antipsychotic, cardiovascular and gastrokinetic activity and their preparations; it further relates to compositions comprising them, as well as their use as a medicine.
An article by Monkovic et al. (J. Med. Chem. (1973), 16(4), p. 403-407) describes the synthesis of (±)-3,3a,8,12b-tetrahydro-N-methyl-2H-dibenzo[3,4:6,7]-cyclohepta-[1,2-b]furan-2-methanamine oxalic acid. Said compound was synthesized as potential antidepressant; however, it was found that this particular tetrahydrofurfurylamine derivative was inactive as antidepressant at a dose of 300 mg/kg. Compounds of similar structure are disclosed in U.S. Pat. No. 4,145,434, published on Mar. 20, 1979, and involve dibenzo(cyclohepta-, oxepino-, thiepino-) pyrrolidine derivatives as well as dibenzopyrrolidino azepine derivatives, having CNS-depressant, antihistamine and antiserotonin activities. The present compounds differ therefrom structurally by the presence of a tetrahydrofuran ring instead of a pyrrolidine ring, and are further distinguished by valuable pharmacological properties, in particular, they suppress mCPP (metachlorophenylpiperazine) induced effects in rats.
This invention concerns compounds of formula (I)
the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein:
n is zero, 1, 2, 3, 4, 5, or 6;
p is zero, 1, 2, 3 or 4;
q is zero, 1, 2, 3 or 4;
r is zero, 1, 2, 3, 4 or 5;
R
1
and R
2
each independently are hydrogen; C
1-6
alkyl; C
1-6
alkylcarbonyl; halomethylcarbonyl; C
1-6
alkyl substituted with hydroxy, C
1-6
alkyloxy, carboxyl, C
1-6
alkylcarbonyloxy, C
1-6
alkyloxycarbonyl or aryl; or R
1
and R
2
taken together with the nitrogen atom to which they are attached may form a morpholinyl ring or a radical of formula:
 wherein:
R
9
, R
10
, R
11
and R
12
each independently are hydrogen, halo, halomethyl, or C
1-6
alkyl;
m is zero, 1, 2, or 3;
R
13
, R
14
, R
15
and R
16
each independently are hydrogen, C
1-6
alkyl, aryl or arylcarbonyl; or
R
15
and R
16
taken together may form a bivalent radical C
4-5
alkanediyl;
R
17
is hydrogen; C
1-6
alkyl; C
1-6
alkylcarbonyl; halomethylcarbonyl; C
1-6
alkyloxycarbonyl; aryl; di(aryl)methyl; C
1-6
alkyl substituted with hydroxy, C
1-6
alkyloxy, carboxyl, C
1-6
alkylcarbonyloxy, C
1-6
alkyloxycarbonyl or aryl;
each R
3
independently is halo, cyano, hydroxy, halomethyl, halomethoxy, carboxyl, nitro, amino, mono- or di(C
1-6
alkyl)amino, C
1-6
alkylcarbonylamino, aminosulfonyl, mono- or di(C
1-6
alkyl)aminosulfonyl, C
1-6
alkyl, C
1-6
alkyloxy, C
1-6
alkylcarbonyl, C
1-6
alkyloxycarbonyl;
each R
4
independently is halo, cyano, hydroxy, halomethyl, halomethoxy, carboxyl, nitro, amino, mono- or di(C
1-6
alkyl)amino, C
1-6
alkylcarbonylamino, aminosulfonyl, mono- or di(C
1-6
alkyl)aminosulfonyl, C
1-6
alkyl, C
1-6
alkyloxy, C
1-6
alkylcarbonyl, C
1-6
alkyloxycarbonyl;
each R
5
independently is C
1-6
alkyl, cyano or halomethyl;
X is CR
6
R
7
, NR
8,
O, S, S(═O) or S(═O)
2
; wherein
R
6
and R
7
each independently are hydrogen, hydroxy, C
1-6
alkyl, halomethyl, C
1-6
alkyloxy or R
6
and R
7
taken together may form methylene; mono- or di(cyano)methylene; a bivalent radical of formula —(CH
2
)
2
—, —(CH
2
)
3
—, —(CH
2
)
4
—, —(CH
2
)
5
—, —O—(CH
2
)
2
—O—, —O—(CH
2
)
3
—O—; or, together with the carbon atom to which they are attached, a carbonyl;
R
8
is hydrogen, C
1-6
alkyl, C
1-6
alkylcarbonyl, arylcarbonyl, arylC
1-6
alkylcarbonyl, C
1-6
alkylsulfonyl, arylsulfonyl or arylC
1-6
alkylsulfonyl;
aryl is phenyl; or phenyl substituted with 1, 2 or 3 substituents selected from halo, hydroxy, C
1-6
alkyl and halomethyl;
provided that the compound is other than (±)-3,3a,8,12b-tetrahydro-N-methyl-2H-dibenzo[3,4:6,7]-cyclohepta[1,2-b]furan-2-methanamine oxalic acid.
In the foregoing definitions C
1-6
alkyl defines straight and branch chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylpropyl, 1,1-dimethylethyl, pentyl, hexyl; C
4-5
alkanediyl defines bivalent straight and branch chained saturated hydrocarbon radicals having from 4 to 5 carbon atoms such as, for example, 1,4-butanediyl, 1,5-pentanediyl; halo is generic to fluoro, chloro, bromo and iodo. The term monocyanomethylene stands for a radical of formula ═CHCN, and dicyanomethylene for a radical of formula ═C(CN)
2
. The term halomethyl is meant to include mono-, di-, and trihalomethyl. Examples of halomethyl are fluoromethyl, difluoromethyl and particularly trifluoromethyl. In case R
6
and R
7
taken together form a bivalent radical of formula —(CH
2
)
2
—, —(CH
2
)
3
—, —(CH
2
)
4
—, —(CH
2
)
5
—, —O—(CH
2
)
2
—O— or —O—(CH
2
)
3
—O—, the compounds of formula (I) are spiro compounds.
The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic base and acid addition salt forms which the compounds of formula (I) are able to form. The acid addition salt form of a compound of formula (I) that occurs in its free form as a base can be obtained by treating the free base form of the compound of formula (I) with an appropriate acid such as an inorganic acid, for example, hydrohalic acid, e.g. hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like acids; or an organic acid, such as, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
The compounds of formula (I) containing acidic protons may be converted into their therapeutically active non-toxic base, i.e. metal or amine, addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamnine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely said salt forms can be converted into the free forms by treatment with an appropriate base or acid.
The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like.
The N-oxide forms of the compounds of formula (I) are meant to comprise those compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide, particularly those N-oxides wherein the nitrogen bearing the R
1
and R
2
substituents is N-oxidized.
The term “stereochemically isomeric forms” as used hereinbefore and hereinafter defines all the possible isomeric forms in which the compounds of formula (I) may occur. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture, and in particular the racemic mixture, of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. Stereochemically isomeric forms of the compounds of formula (I) and mixtures of such forms are intended to be encompassed by formula (I).
The numbering of the tetracyclic ring-system present in the compounds of formula (I), as defined by Chemical Abstracts nomenclature is shown in formula (I′).
The compounds of formula (I) have at least three asymmetric centers, namely carbon atom 2, carbon atom 3a and carbon atom 12b. Said asymmetric centers and any other asymmetric center which may be present, are indicated by the descriptors R and S.
When a monocyanomethylene moiety is present in the compounds of formula (I), said moiety may have the E- or Z-configuration.
The subst

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