Antagonists of calcitonin gene-related peptide

Details Antagonists of calcitonin gene-related peptide Antagonists of calcitonin gene-related peptide

2000-03-10

2001-11-06

Russel, Jeffrey E. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S183000, C514S212010, C514S218000, C514S241000, C514S247000, C514S277000, C514S316000, C514S331000, C540S484000, C540S553000, C540S597000, C544S215000, C544S238000, C544S335000, C544S360000, C546S184000, C546S190000, C546S192000, C546S230000, C546S233000, C546S234000

Reexamination Certificate

active

06313097

ABSTRACT:

DESCRIPTION OF THE INVENTION
The present invention relates to modified amino acid amides of general formula
the tautomers, the diastereomers, the enantiomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, pharmaceutical compositions containing these compounds, their use and processes for preparing them.
In the above general formula I:
R denotes a 1-piperidinyl group, which is substituted in the 4 position by a mono- or di-unsaturated 5- to 7-membered aza, diaza or triaza heterocyclic group bound via a nitrogen atom, which contains one or two carbonyl groups linked to a nitrogen atom, whilst the abovementioned heterocyclic groups may be substituted at a carbon atom by an optionally substituted phenyl group, an olefinic double bond of one of the abovementioned unsaturated heterocyclic groups may be condensed with a benzene, pyridine, diazine, 1,3-oxazole, thiophene, furan, thiazole, pyrrole, N-methyl-pyrrole, quinoline, imidazole or N-methyl-imidazole ring or two olefinic double bonds in one of the abovementioned unsaturated heterocyclic groups may be benzocondensed, and wherein the abovementioned phenyl group as well as the benzo-, thieno-, pyrido- and diazino-condensed heterocyclic groups may additionally be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, by alkyl groups, cycloalkyl groups with 3 to 8 carbon atoms, nitro, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkylaminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, methylenedioxy, aminocarbonylamino, aminocarbonylaminoalkyl, alkylaminocarbonylamino, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl groups, whilst the substituents may be identical or different,
Y denotes the divalent groups
wherein R
9
denotes an alkyl group with 1 to 4 carbon atoms or a phenyl group optionally substituted by a halogen atom or a methyl or methoxy group,
X
1
, X
2
and X
3
, which may be identical or different, denote the hydrogen atom, the fluorine, chlorine or bromine atom, a branched or unbranched alkyl group, an alkoxy, trifluoromethyl, dialkylaminoalkyl, dialkylaminoalkoxy, nitro, hydroxy, amino, acetylamino, methylsulfonyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl group,
A denotes a bond or the divalent group
linked via the —CO group to the NR
1
R
2
group of formula I, wherein
R
7
denotes the hydrogen atom or the methyl group,
R
8
denotes the hydrogen atom, the methyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl or acetyl group,
R
1
denotes the hydrogen atom, an alkyl group with 1 to 7 carbon atoms, which may be substituted in the &ohgr; position by a cyclohexyl, phenyl, pyridinyl, diazinyl, hydroxy, amino, alkylamino, dialkylamino, carboxy, aminocarbonyl, aminocarbonylamino, acetylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-(1-piperidinyl)-1-piperidinyl, 4-morpholinyl, hexahydro-1H-1-azepinyl, [bis-(2-hydroxyethyl)]amino, 4-alkyl-1-piperazinyl or 4-(&ohgr;-hydroxyalkyl)-1-piperazinyl group, a phenyl or pyridinyl group, whilst the abovementioned heterocyclic groups and phenyl groups may additionally be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, by methyl, alkoxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, cyano, methylsulfonyloxy, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl groups and the substituents may be identical or different,
R
2
denotes the hydrogen atom or an alkyl group with 1 to 3 carbon atoms optionally substituted by a phenyl or pyridinyl group or
R
1
and R
2
together with the included nitrogen atom denote a group of general formula III
wherein
Y
1
denotes the carbon atom or, if R
4
denotes a free pair of electrons, it may also represent the nitrogen atom,
m denotes the numbers 0, 1 or 2,
n denotes the numbers 0, 1 or 2,
R
3
denotes the hydrogen atom, an amino, alkylamino, dialkylamino, alkyl, cycloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminoiminomethyl, aminocarbonylamino, alkylaminocarbonylamino, cycloalkylaminocarbonylamino, phenylaminocarbonylamino, aminocarbonylalkyl, aminocarbonylaminoalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl or carboxy group, a phenyl, pyridinyl, diazinyl, 1-naphthyl, 2-naphthyl, pyridinylcarbonyl or phenylcarbonyl group, each of which may be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, by alkyl, alkoxy, methylsulfonyloxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, aminocarbonylamino, aminocarbonylaminomethyl, cyano, carboxy, carbalkoxy, carboxyalkyl, carbalkoxyalkyl, alkanoyl, &ohgr;-(dialkylamino)alkanoyl, &ohgr;-(dialkylamino)alkyl, &ohgr;-(dialkylamino)hydroxyalkyl, &ohgr;-(carboxy)alkanoyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl groups, whilst the substituents may be identical or different,
a 4- to 10-membered azacycloalkyl group, a 5- to 10-membered oxaza, thiaza or diazacycloalkyl group, or a 6- to 10-membered azabicycloalkyl group, whilst the abovementioned mono- and bicyclic heterocyclic groups are bound via a nitrogen or carbon atom,
a 1-alkyl-4-piperidinylcarbonyl or 4-alkyl-1-piperazinylcarbonyl group, whilst the abovementioned mono- and bicyclic heterocyclic groups as well as the 1-alkyl-4-piperidinylcarbonyl and 4-alkyl-1-piperazinylcarbonyl group may be substituted in the ring by an alkyl group with 1 to 7 carbon atoms, by an alkanoyl, dialkylamino, phenylcarbonyl, pyridinylcarbonyl, carboxyalkanoyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylsulfonyl, cycloalkyl or cycloalkylalkyl group, by a cycloalkylcarbonyl, azacycloalkylcarbonyl, diazacycloalkylcarbonyl or oxazacycloalkylcarbonyl group optionally alkyl-substituted in the ring, whilst the alicyclic moieties contained in these substituents contain 3 to 10 ring members and the heteroalicyclic moieties each contain 4 to 10 ring members and the abovementioned phenyl and pyridinyl groups may in turn be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl, alkoxy, methylsulfonyloxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, aminocarbonylamino, aminocarbonylaminomethyl, cyano, carboxy, carbalkoxy, carboxyalkyl, carbalkoxyalkyl, alkanoyl, &ohgr;-(dialkylamino)alkanoyl, &ohgr;-(carboxy)alkanoyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl groups, whilst the substituents may be identical or different, or
R
3
together with R
4
and Y
1
denote a 4- to 7-membered cycloaliphatic ring, in which a methylene group may be replaced by a group —NH— or —N(alkyl)-, whilst a hydrogen atom bound to a nitrogen atom within the group R
3
may be replaced by a protecting group,
R
4
denotes a hydrogen atom, an alkyl group with 1 to 4 carbon atoms, whilst an unbranched alkyl group may be substituted in the &ohgr; position by a phenyl, pyridinyl, diazinyl, amino, alkylamino, dialkylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-methyl-1-piperazinyl, 4-morpholinyl or hexahydro-1H-1-azepinyl group, an alkoxycarbonyl, the cyano or aminocarbonyl group or a free pair of electrons, if Y
1
denotes a nitrogen atom, and
R
5
and R
6
each denote a hydrogen atom or, if Y
1
is a carbon atom, R
4
together with R
6
also denotes another carbon-carbon bond, whilst R
3
is as hereinbefore defined and R
5
denotes

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