1-sulfonyl pyrrolidine derivatives

Details 1-sulfonyl pyrrolidine derivatives 1-sulfonyl pyrrolidine derivatives

2001-06-13

2003-07-08

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S542000

Reexamination Certificate

active

06589978

ABSTRACT:

FIELD OF INVENTION
The present invention is generally related to 1-sulfonyl pyrrolidine derivitives showing affinity toward metabotropic glutamate receptors.
BACKGROUND
In the central nervous system (CNS) the transmission of stimuli takes place by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreceptor.
L-glutamic acid, the most commonly occurring neurotransmitter in the CNS, plays a critical role in a large number of physiological processes. The glutamate-dependent stimulus receptors are divided into two main groups. The first main group, namely the ionotropic receptors, forms ligand-controlled ion channels. The metabotropic glutamate receptors (mGluR) belong to the second main group and, furthermore, belong to the family of G-protein-coupled receptors.
At present, eight different members of these mGluR are known and of these some even have sub-types. On the basis of structural parameters, the different influences on the synthesis of secondary metabolites and the different affinity to low-molecular weight chemical compounds, these eight receptors can be sub-divided into three sub-groups:
mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.
Ligands of metabotropic glutamate receptors belonging to the first group can be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits, as well as chronic and acute pain.
Other treatable indications in this connection are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depressions.
SUMMARY
The present invention is a compound of the formula
wherein
R
1
signifies hydrogen or aryl, which is unsubstituted or substituted by halogen;
R
2
signifies aryl, which is unsubstituted or substituted by halogen or lower alkyl;
R
3
signifies —OR′, cyano, halogen, N-hydroxy-amidino, —C(O)—OR, —C(O)NR′R″, —N(R′)—C(O)—R
4
, —N(R′)—S(O)
2
—R, —N(R′)—C(S)—NR′″R or a 5- or 6-membered heteroaryl ring containing 1 to 4 N or O heteroatoms, said ring being unsubstituted or substituted by lower alkyl or cycloalkyl;
R
4
signifies cycloalkyl, phenyl or lower alkyl, which is unsubstituted or substituted by halogen;
R signifies lower alkyl;
R′ and R′″ signify hydrogen, lower alkyl or cycloalkyl-lower alkyl;
R″ signifies hydrogen, lower alkyl or lower alkyl substituted by a 5- or 6-membered heteroaryl ring containing from 1 to 4 N or O heteroatoms, said ring being unsubstituted or substituted by lower alkyl or cycloalkyl;
n is an integer from 0 to 5;
or its pharmaceutically acceptable salts.
It has been surprisingly found that the compounds of formula I possess affinity towards metabotropic glutamate receptors. Compounds of formula I are distinguished by valuable therapeutic properties.
Objects of the present invention are compounds of formula I and pharmaceutically acceptable salts thereof, racemic mixtures and their corresponding enantiomers, the above-mentioned compounds as pharmaceutically active substances, their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of the compounds in accordance with the invention in the control or prevention of illnesses of the aforementioned kind, and, respectively, for the production of corresponding medicaments.
DETAILED DESCRIPTION
The present invention includes a compound of the formula
wherein
R
1
signifies hydrogen or aryl, which is unsubstituted or substituted by halogen;
R
2
signifies aryl, which is unsubstituted or substituted by halogen or lower alkyl;
R
3
signifies —OR′, cyano, halogen, N-hydroxy-amidino, —C(O)—OR, —C(O)NR′R″, —N(R′)—C(O)—R
4
, —N(R′)—S(O)
2
—R, —N(R′)—C(S)—NR′″R or a 5- or 6-membered heteroaryl ring containing from 1 to 4 N or O heteroatoms, said ring being unsubstituted or substituted by lower alkyl or cycloalkyl;
R
4
signifies cycloalkyl, phenyl or lower alkyl, which is unsubstituted or substituted by halogen;
R signifies lower alkyl;
R′ and R′″ signify hydrogen, lower alkyl or cycloalkyl-lower alkyl, signifies hydrogen, lower alkyl or lower alkyl substituted by a 5- or 6-membered heteroaryl ring containing from 1 to 4 N or O heteroatoms, said ring being unsubstituted or substituted by lower alkyl or cycloalkyl, and
n is an integer from 0 to 5;
or pharmaceutically acceptable salts thereof.
Preferred compounds of formula I include a compound wherein R
1
is hydrogen; R
2
is aryl unsubstituted or substituted by halogen or lower alkyl; R
3
and n are as defined above. An additional preferred compound includes a compound wherein R
2
is p-tolyl and n is 3. Yet an additional preferred compound includes R
3
as N(R′)—C(O)—R
4
′ or 5- or 6-membered heteroaryl groups containing 1 to 4 heteroatoms selected independently from each other from N or O, which are unsubstituted or substituted by lower alkyl or cycloalkyl, and R
4
is as defined above.
A further preferred compound has the structure
wherein R
3
and n are as above; and wherein R
5
is hydrogen, halogen or lower alkyl. Additionally, compound I-A wherein R
3
is —OR′, N-hydroxy-amidino, —C(O)NR′R″ or —N(R′)—C(O)—R
4
; R
5
is halogen and n is 2 or 3 is preferred. Compound I-A is also preferred when R
3
is OR′; R
5
is ethyl; R′ is as above and n is 1. Another preferred compound of formula I-A includes R
3
being a 5- or 6-membered heteroaryl ring containing from 1 to 4 heteroatoms selected independently from each other from N or O, which is unsubsituted or substituted by lower alkyl or cycloalkyl with n as an integer between 0 and 5.
Another preferred compound of the present invention has the structure
wherein R
3
and n are as above.
A compound of formula I-B when R
3
is an unsubstituted 5-membered heteroaryl group containing from 1 to 4 heteroatoms selected independently from each other from N or O is also preferred. Yet another preferred compound of formula I-B includes R
3
as an unsubstituted 5-membered heteroaryl group containing from 1 to 4 nitrogen atoms and n is 0, 1 or 2. A compound of formula I-B is also preferred when the heteroaryl group includes at least one oxygen and n is 0, 1 or 2 or when n is 3, 4 or 5. An additional preferred compound of formula I-B includes R
3
being a substituted 5-membered heteroaryl group containing 1 to 4 heteroatoms selected independently from each other from N or O; the 5-membered heteroaryl group containing from 1 to 4 nitrogen atoms with n as 0, 1 or 2; or the case where the substituted 5-membered heteroaryl group contains from 1 to 4 nitrogen atoms and n is 3, 4 or 5. An additional preferred compound of formula I-B includes R
3
being a substituted 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from N or O and containing at least one N and at least one O wherein n is 0, 1 or 2; or when n is 3, 4, or 5.
Yet another preferred compound of formula I-B includes R
3
being selected from —C(O)—OR, —C(O)NR′R″, cyano, halogen, N-hydroxy-amidino, —N(R′)—C(O)—R
4
—C(O)—OR, —N(R′)—S(O
2
)—R and —N(R′)—C(S)—NR′″R, wherein R′, R″, R′″, R
4
and R are as defined above.
Another preferred compound of formula I has the structure
wherein R
3
and n are as defined above. Ano

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