Benzimidazolinyl piperidines as CGRP ligands

Details Benzimidazolinyl piperidines as CGRP ligands Benzimidazolinyl piperidines as CGRP ligands

2001-05-30

2003-04-22

Chang, Ceila (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S321000, C514S323000, C546S199000, C546S202000, C546S205000

Reexamination Certificate

active

06552043

ABSTRACT:

The present invention relates to benzimidazolinylpiperidine derivatives useful as ligands for CGRP (Calcitonin Gene-Related Peptide) receptors, processes for their preparation, their use in therapy, pharmaceutical compositions comprising them and methods of treatment using them.
CGRP is a naturally occurring 37-amino acid peptide that is generated by tissue-specific alternate processing of calcitonin messenger RNA and is widely distributed in the central and peripheral nervous system. CGRP is localised predominantly in sensory afferent and central neurons and exhibits several biological actions, including vasodilation. CGRP is expressed in &agr;- and &bgr;-forms that vary by one and three amino acids in the rat and human, respectively.
CGRP&agr; and CGRP&bgr; display similar biological properties. When released from the cell, CGRP initiates its biological responses by binding to specific cell surface receptors that are predominantly coupled to the activation of adenylyl cyclase. CGRP receptors have been identified and pharmacologically evaluated in several tissues and cells, including those of brain, cardiovascular, endothelial, and smooth muscle origin.
Based on pharmacological properties, these receptors are divided into at least two subtypes, denoted CGRP
1
and CGRP
2
. Human (h) CGRP-(8-37)&agr;, a fragment of CGRP that lacks seven N-terminal amino acid residues, is a selective antagonist of CGRP
1
-Rs, whereas the linear analogue of CGRP, diacetoamido methyl cysteine CGRP ([Cys(ACM)2,7]CGRP), is a selective agonist of CGRP
2
-Rs.
We have now surprisingly found a class of compounds which are ligands, and preferably antagonists for CGRP receptors. In particular, they preferably bind selectively to human rather than rodent CGRP.
wherein:
R
1
is naphthyl or benzothienyl which is unsubstituted or substituted at up to three substitutable positions independently by C
1-6
alkyl, halogen, C
1-6
alkoxy, CF
3
, OCF
3
, NO
2
, CN, methylenedioxy or ethylenedioxy;
R
2
is hydrogen, C
1-8
alkyl, —(CH
2
)
t
-aryl wherein aryl is selected from phenyl, biphenyl and naphthyl, —(CH
2
)
t
-heteroaryl wherin heteroaryl is selected from tetrazolyl, oxadiazolyl, thiadiazolyl, triazolyl and pyrazinyl, —(CH
2
)
q
C(O)OR
6
, —(CH
2
)
q
OR
6
, —(CH
2
)
q
OC(O)R
6
, —(CH
2
)
q
C(O)R
6
, —(CH
2
)
q
C(O)(CH
2
)
t
aryl, —(CH
2
)
q
N(R
6
)C(O)R
6
, —(CH
2
)
q
C(O)N(R
6
)
2
, —(CH
2
)
q
N(R
6
)SO
2
R
6
, —(CH
2
)
q
N(R
6
)C(O)N(R
6
)
2
, —(CH
2
)
q
OC(O)N(R
6
)
2
, —(CH
2
)
q
N(R
6
)C(O)OR
6
, —(CH
2
)
q
N(R
6
)SO
2
N(R
6
)
2
and —(CH
2
)
q
S(O)
m
l R
6
;
R
3
is NH
2
;
R
4
is hydrogen, C
1-6
alkyl, C
1-6
alkoxy, halogen, OCF
3
or CF
3
;
R
5
is hydrogen, C
1-6
alkyl, C
1-6
alkoxy, halogen, OCF
3
or CF
3
;
R
6
is hydrogen, C
1-8
alkyl or C
3-7
cycloalkyl, and when two R
6
groups are present and both represent C
1-8
alkyl they may optionally together with the atom to which they are both attached form a C
3-8
ring;
Q is —(CH
2
)
x
—C(R
7
)(R
7a
)—(CH
2
)
y
— or —(CH
2
)
x
—V—(CH
2
)
y
—;
R
7
and R
7a
are independently chosen from hydrogen, CF
3
, halogen, C
1-6
alkyl and C
1-6
alkoxy;
V is a C
3-8
non-aromatic cyclic or bicyclic ring or an aromatic ring which is benzene or naphthalene, said ring being unsubstituted or substituted at up to three substitutable positions independently by C
1-6
alkyl, C
1-6
alkoxy, halogen, OCF
3
, CF
3
, CN, NO
2
, methylenedioxy or ethylenedioxy;
m is 0, 1 or 2;
q is 0, 1, 2, 3 or 4;
t is 0, 1, 2 or 3;
x and y are independently 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable salt thereof.
R
1
is preferably unsubstituted or substituted with one or two groups selected from methyl, methoxy, CF
3
or halogen. Most preferably R
1
is unsubstituted.
R
2
is preferably hydrogen, methyl or (CH
2
)
q
C(O)OR
6
, for example R
2
is
t
butyloxycarbonyl or hydrogen.
R
4
is preferably hydrogen, methyl, methoxy, halogen, OCF
3
or CF
3
. In particular, R
4
is hydrogen.
R
5
is preferably hydrogen, methyl, methoxy, halogen OCF
3
or CF
3
. In particular R
5
is hydrogen.
R
6
is preferably hydrogen, C
1-4
alkyl or C
5-6
cycloalkyl. In particular R
6
may be hydrogen or
t
butyl.
R
7
and R
7a
are preferably independently chosen from hydrogen, halogen, CF
3
, methyl, methoxy and OCF
3
. In particular both are hydrogen.
V is preferably an unsubstituted or substituted C
5-6
cycloalkyl or benzene. It is to be noted that the group (CH
2
)
y
or, as the case may be R
3
is attached to any position of this ring, but the 3- and 4-positions are preferred. Most particularly V is cyclohexane or benzene.
m is preferably 0 or 2
q is preferably 0, 1 or 2
t is preferably 0 or 1
x+y is preferably 0, 1, 2, 3 or 4, in particular 0 or 3.
Thus there is a preferred subclass of compounds of formula Ia:
wherein R
1
is unsubstituted naphthyl or benzothienyl;
R
2
is hydrogen or C(O)OR
6
;
R
6
is C
1-4
alkyl;
Q is —(CH
2
)
x
—C(R
7
)(R
7a
)—(CH
2
)
y
— or —(CH
2
)
x
—V—(CH
2
)
y
—;
V is cycloalkyl or benzene;
x is 0, 1 or 2;
y is 0, 1 or 2;
or a pharmaceutically acceptable salt thereof.
The term “alkyl” refers to a monovalent alkane (hydrocarbon) derived radical which may be straight, branched or cyclic. Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl and t-butyl. “Alkoxy” groups are to be construed analogously.
The term “C
3-8
cyclic ring” includes groups such as cyclopentyl, cyclohexyl and methylcyclohexyl.
The term “halogen” is intended to include fluorine, chlorine, bromine and iodine.
Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts include the following:
Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate, Camsylate, Carbonate, Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluconate, Glutamate, Hydrobromide, Hydrochloride, Hydroxynaphthoate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate, Mucate, Napsylate, Nitrate, N-methylglucamine ammonium salt, Oleate, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate, Phosphate/diphosphate, Polygalacturonate, Salicylate, Stearate, Sulfate, Subacetate, Succinate, Tannate, Tartrate, Tosylate, and Valerate. A preferred salt is Hydrochloride.
The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds are contemplated to be within the scope of the present invention. Therefore, where a compound is chiral, the separate enantiomers, substantially free of the other, are included within the scope of the invention; further included are all mixtures of the two enantiomers. Also included within the scope of the invention are polymorphs and hydrates of the compounds of the instant invention.
Asymmetric centers may be present in the compounds of the instant invention depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixture and as pure or partially purified compounds are included within the ambit of this invention.
A prefered chiral configuration of the compounds of formula I is:
The ability of the compounds of the present invention to act as ligands for CGRP makes them useful as pharmacological agents for humans and animals, but particularly humans, for the treatment and prevention of disorders where CGRP may be involved. Such disorders include migraine, pain, cardiovascular disorders, inflammation, diabetes, Reynaud's syndrome, peripheral arterial insufficiency, subarachnoid and other cranial haemorrhages and as antitumour agents by controlling the flow of blood to tumours. Of these conditions, the treatment of migraine is particularly important.
The present invention therefore also provides a pharmaceutical composition comprising a compound of the

Affiliated with

Also associated with

Rating

Benzimidazolinyl piperidines as CGRP ligands does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Benzimidazolinyl piperidines as CGRP ligands, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Benzimidazolinyl piperidines as CGRP ligands will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3105400