2H-tetrazole-amide compounds with therapeutic activity as...

Details 2H-tetrazole-amide compounds with therapeutic activity as... 2H-tetrazole-amide compounds with therapeutic activity as...

2001-06-27

2002-06-04

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S381000, C548S251000

Reexamination Certificate

active

06399641

ABSTRACT:

FIELD OF INVENTION
The present invention is generally related to novel 2H-tetrazole-5-yl amide compounds, a process for making the compounds, a medicament incorporating the compounds and a method of treatment utilizing the compounds as metabotropic glutamate receptor agonists.
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 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 mGluRs' are known and of these some even have sub-types. On the basis of structural parameters, the different second messager signalling pathways 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 by administration of agonists of metabotropic gluamate receptors include 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 depression.
SUMMARY
The present invention is includes 2H-tetrazole-5-yl-amide derivatives of the formula
wherein
R
1
is hydrogen, lower alkyl, —(CH
2
)
n
—CF
3
, —(CH
2
)
n
—CHF
2
, —(CH
2
)
n
—CN, —(CH
2
)
n
-cycloalkyl, —(CH
2
)
n
—O-lower alkyl, —(CH
2
)
n
—O-cycloalkyl or —(CH
2
)
n
—C(O)O-lower alkyl;
R
2
is hydrogen, lower alkyl, lower alkoxy, halogen, —C(O)-lower alkyl, —C(O)OH, —C(O)O-lower alkyl, —NR
3
R
4
or —C(O)—NR
3
R
4
and wherein R
3
and R
4
are hydrogen or lower alkyl;
X and X′ are taken together to form —O—, —S—, —CH
2
, —OCH
2
—, a bridge between the two rings or individually are two hydrogen atoms not capable of forming a bridge between the two rings; and
n signifies 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable salt thereof.
A compound of structure I and a pharmaceutically acceptable salt thereof are novel and are distinguished by valuable therapeutic properties.
It has been surprisingly found that the compounds of formula I are group 1 metabotropic glutamate receptor agonists (mGluR).
DETAILED DESCRIPTION
A preferred compound of formula 1 has the structure formula 1A
Preferred compounds having structure 1A include compounds having R
1
being lower alkyl, —(CH
2
)
n
—C(O)O-lower alkyl, —(CH
2
)
n
-cycloalkyl, —(CH
2
)
n
—O-lower alkyl, —(CH
2
)
n
—CF
3
, —(CH
2
)
n
—CHF
2
, or —(CH
2
)
n
—CN and R
2
being hydrogen.
The following are examples of preferred compounds having the structure of formula 1A:
N-(2-methyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide,
N-(2-ethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide,
N-(2-cyclopropylmethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide,
N-(2-isopropyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide,
2,2-diphenyl-N-[2-(2,2,2-trifluoro-ethyl)-2H-tetrazol-5-yl]-acetamide,
2,2-diphenyl-N-(2-propyl-2H-tetrazol-5-yl)-acetamide,
N-(2-methoxymethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide,
N-(2-tert-butyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide,
N-(2-difluoromethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide,
N-(2-cyanomethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide and
(5-diphenylacetylamino-tetrazol-2-yl)-acetic acid methyl ester.
Another preferred compound of formula 1 has the structure 1B
wherein X and X′ are joined together as —O— thereby forming a bridge between the rings.
Preferred compounds having structure 1B include compounds having R
1
being lower alkyl, —( CH
2
)
n
-cycloalkyl, —(CH
2
)
n
—CF
3
, —(CH
2
)
n
—CHF
2
, —(CH
2
)
n
—CN, —(CH
2
)
n
—C(O)O-lower alkyl or —(CH
2
)
n
—O-lower alkyl and R
2
being hydrogen and R
1
being lower alkyl and R
2
being lower alkoxy.
The following are examples of preferred compounds having the structure 1B:
9H-xanthene-9-carboxylic acid (2-methyl-2H-tetrazol-5-yl)-amide,
9H-xanthene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide,
9H-xanthene-9-carboxylic acid (2-cyclopropylmethyl-2H-tetrazol-5-yl)-amide,
9H-xanthene-9-carboxylic acid (2-isopropyl-2H-tetrazol-5-yl)-amide,
9H-xanthene-9-carboxylic acid [2-(2,2,2-trifluoro-ethyl)-2H-tetrazol-5-yl]-amide,
9H-xanthene-9-carboxylic acid (2-propyl-2H-tetrazol-5-yl)-amide,
9H-xanthene-9-carboxylic acid (2-methoxymethyl-2H-tetrazol-5-yl)-amide,
9H-xanthene-9-carboxylic acid (2-tert-butyl-2H-tetrazol-5-yl)-amide,
9H-xanthene-9-carboxylic acid (2-difluoromethyl-2H-tetrazol-5-yl)-amide,
9H-xanthene-9-carboxylic acid (2-cyanomethyl-2H-tetrazol-5-yl)-amide,
{5-[(9H-xanthene-9-carbonyl)-amino]-tetrazol-2-yl}-acetic acid methyl ester,
(RS)-1-methoxy-9H-xanthene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide,
(RS)-2-methoxy-9H-xanthene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide and
(RS)-4-Methoxy-9H-xanthene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide
Another preferred compound from formula 1 is a compound with the structure of formula 1C.
wherein X and X′ are joined together as —S—, thereby forming a bridge between the rings. A preferred example of the compound of formula 1C is 9H-thioxanthene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide.
Yet another preferred compound of formula 1 has the structure 1D.
wherein X and X′ are joined together as —CH
2
—, thereby forming a bridge between the rings. A preferred example of a compound with the structure of formula 1D is 9,10-dihydro-anthracene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide.
Another preferred compound of formula I has the structure IE
wherein X and X′ are joined together as —OCH
2
—, thereby forming a bridge between the rings; and wherein R
1
and R
2
are as defined in formula I above. A preferred compound of formula 1E is (RS)-6,11-dihydro-dibenzo [b,e]oxepine-11-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide.
Also preferred are compounds of the present invention of formula IA, IB, IC, ID and IE, wherein R
2
is hydrogen.
The compound of the invention embraces all stereoisomeric forms of formula I in addition to the racemates.
The term “lower alkyl” used in the present description denotes straight-chain or branched saturated hydrocarbon residues with 1-7 carbon atoms, preferably with 1-4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl and the like.
The term “lower alkoxy” denotes a lower alkyl residue in the sense of the foregoing definition bonded via an oxygen atom.
The term “cycloalkyl” embraces cyclic alkyl rings having between 3 to 7 carbon atoms.
The compounds of formula I and their pharmaceutically acceptable salts can be manufactured by processes, which comprises
with a compound of formula
to a compound of formula
wherein the substituents are as designated above and, if desired, converting a functional group in a compound of formula I into another functional group and, if desired, converting a compound of formula I into

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