Abeo-ergoline derivatives as 5HT1A ligands

Details Abeo-ergoline derivatives as 5HT1A ligands Abeo-ergoline derivatives as 5HT1A ligands

1997-12-29

2001-09-04

Morris, Patricia L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06284896

ABSTRACT:

This invention relates to new 5(10→9)abeo-ergoline derivatives, to processes for their preparation, to their use as medicaments and to a pharmaceutical composition containing them. The novel compounds act upon the central nervous system by binding to 5-HT
1A
receptors and hence can be used for the management of central nervous system pathologies.
The novel compounds of this invention have the formula I
wherein
R
1
is a hydrogen, chlorine or bromine atom or a methyl, methylthio, hydroxy, cyano, carboxamido or nitro group; R
2
is C
1
-C
3
alkyl or an allyl group;
R
3
and R
4
are independently a hydrogen atom, a linear or branched C
1
-C
5
alkyl group, a linear or branched C
3
-C
5
alkenyl group, a C
5
-C
6
cycloalkyl C
1
-C
3
alkyl group, a phenyl-C
1
-C
3
alkyl, a phenyl-C
3
-C
5
alkenyl or phenyl group: which groups are optionally substituted by a C
1
-C
3
alkyl, C
1
-C
3
alkoxy, trifluoromethyl, hydroxy or amino group: or a group of the formula
wherein
R
6
is a hydrogen atom or a C
1
-C
3
alkyl group and R
7
is a phenyl group, a substituted phenyl group as described above or a heterocyclic ring having 5- or 6-ring members including 1 or 2 heteroatoms independently selected from oxygen, sulphur and nitrogen; R
5
, which can be in the 12, 13 or 14 position, is a hydrogen, bromine, fluorine or iodine atom or a methoxy, cyano, carboxamido, nitro, methylthio or trifluoromethyl group or a aroup of the formula NR
8
R
9
, wherein R
8
and R
9
are independently a hydrogen atom or a C
1-3
alkyl, acetyl, trifluoracetyl or methanesulphonyl group. R is a hydrogen atom, a C
1-5
linear or branched alkyl group, a methanesulphonyl group, an acetyl group or a group of formula —C(O)—NR
8
R
9
wherein R
8
and R
9
are as defined above. The dotted line represents the optional presence of a double bond at position 9-10 and/or 2-3.
In the case where a single bond is present in the 9-10 position, the compounds of the invention are of the formula I′
wherein
R, R
1
, R
2
, R
3
, R
4
and R
5
have the above meanings. The wavy lines
mean that the hydrogen atoms and the CHR
3
R
4
group may be at the &agr; or &bgr; position with respect to the plane of the rings.
In the case where a single bond is present in position 2,3, the compounds of the invention are of the formula I″
wherein
R
1
is hydrogen or a methyl group and R
2
, R
3
, R
4
, R
5
and R have the aforementioned meanings.
Pharmaceutically acceptable salts of these abeo-ergoline derivatives are included in the invention.
In the definitions of R
2
, R
3
, R
4
and R, C
1
-C
3
and C
1
-C
5
alkyl groups are intended to include methyl, ethyl, n-propyl, i-propyl, butyl, i-butyl, cyclopropyl and methylcyclopropyl groups.
In the definitions of R
3
and R
4,
phenyl-C
1
-C
3
alkyl group encompasses benzyl and phenethyl groups; phenyl-C
3
-C
5
alkenyl group is intended to include phenylallyl, phenyl butenyl and phenylpropenyl group. The heterocyclic ring which R
7
may represent is, for example, a furanyl, imidazolyl, pyranyl, thienyl, pyrrolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, morpholinyl or thiopyranyl group. More preferred compounds are those of the formula I′ wherein R
1
represents a hydrogen atom, or a cyano or carboxamido group, R
2
represents a methyl group, R
3
represents a hydrogen atom, R
4
represents a group of the formula —CH(OH)Ph, R
5
represents a hydrogen, fluorine or iodine atom or a methoxy, methylthio, trifluoromethyl, carboxamido, or nitro group, or a group of the formula NR
8
R
9
, wherein R
8
and R
9
are independently a hydrogen atom or a C
1-3
alkyl, acetyl, methanesulphonyl or trifluoroacetyl group. The hydrogen at position 5 and the residue at position 8 are both &bgr;.
The present invention also provides a process for the production of the compounds of formula I and their acid addition salts, which process comprises
a) reacting a compound of formula II
wherein
R
2
, R
3
and R
4
have the meanings given above, with a reducing agent such as sodium amalgam in ethanol, aluminium amalgam in aqueous THF (tetrahydrofuran), magnesium in methanol or ethanol at a temperature ranging from 0° to 80° C.
According to the present invention, compounds of formula II are prepared by reaction of an alkaline salt of a compound of formula III
wherein
R
2
is as defined above, either with a compound of formula R
3
Y, wherein R
3
has the meaning given above and Y is a leaving group such as an iodine or bromine atom, or a mesyloxy or tosyloxy group;
or with a compound of the formula R—C(O)—R
7
wherein R
6
and R
7
have the meanings given above and, if desired, reacting an alkaline salt of the resultant compound either with a compound of the formula R
4
Y, wherein R
4
and Y are as defined above, or with a compound of the formula NC(O)R
7
wherein R
6
and R
7
have the meanings given above.
The alkaline salts can be obtained by reaction with strong base such as NaH, KH, ButLi or CH
3
Li in a solvent such as THF, HMPA (hexamethylphosphotriamide) or DME (dimethoxyathane) at a temperature ranging from −800° C. to 0° C.
The reactions for preparing a compound of the formula II are usually carried out in an anhydrous solvent such as THF, HMPA or DME at a temperature of from −80° C. to room temperature, for a period of from 1 hour to 24 hours.
A compound of the formula III may be prepared by reacting a compound of formula IV
wherein
R
2
is as defined above, with oxidizing agents such as hydrogen peroxide in solvents such as methanol, ethanol or acetic acid or with peroxy acids such as m-chloroperbenzoic or peracetic acid in solvents such as DMF, ethanol or chloroform or with sodium periodate in aqueous THF.
Compounds of the formula IV may be prepared either by reacting a compound of the formula V
wherein
R
2
is as defined above with (PhS)
2
and (nBut)
3
P in a solvent such as dioxane, acetonitrile at reflux, or by reacting a compound of the formula (VI)
wherein
R
2
and Y have the same meanings as above with PhSNa in a solvent such as DMF, DMSO (dimethylsulphoxide) or HMPA at a temperature ranging from 80° C. to 120° C.
The compounds of the formula III may also be prepared by reacting a compound of the formula VI as defined above with PhSO
2
Na in a solvent such as HMPA or DMSO at a temperature ranging from 80° C. to 140° C.
The present invention also provides processes for converting a compound of the formula I into another compound of the formula I wherein one or more of R, R
1
and R
5
have been altered.
For example, a conversion may be carried out by reacting a compound of the formula I wherein R
1
and R
5
are hydrogens, with a chlorinating agent such as N—Cl succinimide or sulphuryl chloride, or a brominating agent such as N—Br succinimide, in an inert solvent such as acetonitrile or chloroform; or with a thiomethylating agent such as freshly prepared methylsulphenyl chloride in a solvent such as THF or chloroform; or with an oxiding agent such as N-Br succinimide in tert-butanol.
Following the above methods compounds of the formula I wherein R
1
represents chlorine, bromine, methylthio, and hydroxy group are provided.
When R
1
is a hydroxy group, the compounds of formula I exist almost completely in the tautomeric lactam form.
According to the present invention, a compound of formula I, wherein R
1
is hydrogen, R
2
, R
3
, P and R
5
have the aforementioned meanings and R is hydrogen or a C
1-5
linear or branched alkyl group may be converted into a compound of formula I″, wherein R
1
, R
2
, R
3
, R
4
, R
5
, R have the aforementioned meanings by treatment with zinc dust in concentrated hydrochloric acid or with a reducing agent such as sodium borohydride or sodium cyano borohydride in trifluoroacetic acid.
Exploitation of general techniques such as fractional crystallization, or column chromatography separation allows the separation in pure form of the C-3 diasteroisomers.
According the present invention a compound of formula I, wherein R is an acetyl, methanesulphonyl or dimethylaminocarbonyl group may be

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