US 7,407,963 B2Granted

Cyclopropane CGRP antagonists, medicaments containing these compounds, and method for the production thereof

AssigneeBoehringer Ingelheim Pharma GmbH & Co. KG

InventorsWolfgang Eberlein, Wolfhard Engel, Klaus Rudolf, Henri Doods, Gerhard Hallermayer, Eckhart Bauer

Life of this patent

Estimating the term…

Abstract

A compound of general formula (I) wherein R and R1 are as defined herein, or a tautomer, diastereomer, enantiomer, or salt thereof, particularly the physiologically acceptable salts thereof, which have valuable pharmacological properties, particularly CGRP-antagonistic properties, pharmaceutical compositions containing the compound, their use, and processes for preparing them.

Claims28

Dependent claims

A compound of general formula (I)

wherein:
R is a saturated or mono- or diunsaturated 5- to 7-membered aza, diaza, triaza, oxaza, thiaza, thiadiaza, or S,S-dioxido-thiadiaza heterocyclic group linked via a carbon or nitrogen atom, and
wherein the heterocyclic group of R:
(i) optionally contains one or two carbonyl groups adjacent to a nitrogen atom thereof,
(ii) is optionally substituted by an alkyl group at one of the nitrogen atoms, and
(iii) is optionally substituted at one or two carbon atoms thereof by identical or different substituent groups selected from:
(a) a straight-chain or branched alkyl group, or a phenyl, phenylmethyl, naphthyl, biphenylyl group, or
(b) a pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl, or 1-methylimidazolyl group,
wherein an olefinic double bond thereof is optionally fused with a benzene, pyridine, diazine, 1,3-oxazole, thiophene, furan, thiazole, pyrrole, N-methylpyrrole, quinoline, imidazole, or N-methylimidazole ring, and
wherein the phenyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl, or 1-methylimidazolyl groups contained in R and the benzo, thieno, pyrido- and diazino-fused heterocyclic groups in R are optionally independently additionally mono-, di-, or trisubstituted by:
(a) a fluorine, chlorine, or bromine atom,
(b) an alkyl, dialkylaminoalkoxy, nitro, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, phenyl, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkoxy, hydroxycarbonylalkoxy, carboxy, carboxyalkyl, dialkyl-aminoalkyl, hydroxy, amino, acetylamino, propionylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, [N-alkyl-N-(dialkylaminoalkyl)amino]carbonyl, [(hydroxycarbonylalkyl)amino]carbonyl, [(alkoxycarbonylalkyl)amino]carbonyl, (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, trifluoromethylsulfonyl, or C3-C8 cycloalkyl group,
(c) a 4- to 8-membered alkyleneimino group wherein a methylene group in the 3-, 4-, or 5-position is optionally replaced by an oxygen atom or a methylimino group, or
(d) an alkoxy group optionally substituted in the ω-position by a 5- to 7-membered heteroalicyclic group that is linked via a carbon or nitrogen atom and contains one or two heteroatoms not directly connected to each other selected from oxygen and nitrogen,
wherein multiple substitution of the aforementioned phenyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl, or 1-methylimidazolyl groups contained in R and the benzo, thieno, pyrido- and diazino-fused heterocyclic groups in R by phenyl, C3-C8 cycloalkyl or 4- to 8-membered alkyleneimino groups is excluded;
and
R1 is a phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-formyl-1H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl, 1H-indazol-3-yl, 1-methyl-1H-indazol-3-yl, benzo[b]fur-3-yl, benzo[b]thien-3-yl, pyridinyl, quinolinyl, or isoquinolinyl group,
wherein each group of R1 is optionally independently mono-, di-, or trisubstituted by a substituent group selected from:
(a) a fluorine, chlorine, or bromine atom,
(b) a branched or unbranched alkyl, C3-C8 cycloalkyl, phenylalkyl, alkenyl, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonyl, carboxy, dialkylaminoalkyl, dialkylaminoalkoxy, nitro, hydroxy, amino, acetylamino, propionylamino, methylsulfonyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl, cyano, tetrazolyl, phenyl, pyridinyl, thiazolyl, furyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl, or trifluoromethylsulfonyl group,
wherein the hydroxy, amino, indolyl and imidazolyl groups contained in the abovementioned groups are each optionally independently substituted by a protecting group selected from:
(a) a phenylalkoxycarbonyl group with 1 to 3 carbon atoms in the alkoxy moiety optionally substituted in the phenyl nucleus by a halogen atom, a nitro or phenyl group, or one or two methoxy groups,
(b) an alkoxycarbonyl group having a total of 1 to 5 carbon atoms in the alkyl moiety, or
(c) a formyl, acetyl, trifluoroacetyl, allyloxycarbonyl, 2,2,2-trichloro-(1,1-dimethylethoxy)carbonyl, or 9-fluorenylmethoxycarbonyl group,
wherein all the abovementioned alkyl and alkoxy groups and the alkyl or alkylene moieties present within the other groups specified contain 1 to 5 carbon atoms, unless otherwise stated,
or a diastereomer, enantiomer, or salt thereof.

23 more elements

A compound selected from the group consisting of:

(a) cis-3-{1-[2-(4-chlorobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-2(1H) -quinazolinone;
(b) trans-1-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-1,3-dihydro-4-(3-methoxyphenyl)-2(2H)-imidazolone;
(c) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone;
(d) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-6-bromo-3,4-dihydro-2(1H)-quinazolinone;
(e) trans-1-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-1,3-dihydro-4-phenyl-2(2H)-imidazolone;
(f) trans-1-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-imidazolone;
(g) trans-1-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-1,3-dihydro-4-(3-hydroxyphenyl)-2(2H)-imidazolone;
(h) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-6-hydroxy-2(1H)-quinazolinone;
(i) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-6-[(1,3-dioxolan-2-yl)methoxy]-2(1H)-quinazolinone;
(j) trans-1-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-4-(3,4-dichlorophenyl)-1,3-dihydro-2(2H)-imidazolone;
(k) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-2(1H)-pyrido[4,3-d]pyrimidinone;
(l) trans-1-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-1,3-dihydro-4-(2-methoxyphenyl)-2(2H)-imidazolone;
(m) trans-1-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-4-(3-chlorophenyl)-1,3-dihydro-2(2H)-imidazolone;
(n) trans-1-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-1,3-dihydro-4-(3-nitrophenyl)-2(2H)-imidazolone;
(o) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-2(1H)-pyrido[3,4-d]pyrimidinone;
(p) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-6-[2-(dimethylamino)ethoxy]-2(1H)-quinazolinone;
(q) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-6-(4-methyl-1-piperazinyl)-2(1H)-quinazolinone;
(r) trans-1-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-1,3-dihydro-4-[2-(trifluoromethyl)phenyl]-2(2H)-imidazolone;
(s) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-6-[3-(dimethylamino)propoxy]-2(1H)-quinazolinone;
(t) trans-3-{1-[2-(3,5-dibromo-4-hydroxybenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone;
(u) trans-1-{1-[2-(3,5-dibromo-4-hydroxybenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-1,3-dihydro-4-phenyl-2(2H)-imidazolone;
(v) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-6-(methoxycarbonylmethoxy)-2(1H)-quinazolinone;
(w) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-6-(hydroxycarbonylmethoxy)-2(1H)-quinazolinone;
(x) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-6-[2-(4-morpholinyl)ethoxy]-2(1H)-quinazolinone;
(y) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-7-methoxy-2(1H)-quinazolinone;
(z) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-7-(methoxycarbonylmethoxy)-2(1H)-quinazolinone;
(aa) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-7-carboxy-3,4-dihydro-2(1H)-quinazolinone;
(ab) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-7-methoxycarbonyl-3,4-dihydro-2(1H)-quinazolinone;
(ac) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-1,3-dihydro-2(2H)-imidazo[4,5-c]quinolinone;
(ad) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-7-{[(methoxycarbonylmethyl)amino]carbonyl}-2(1H)-quinazolinone;
(ae) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-7-{[N-(2-dimethylaminoethyl)-N-methylamino]carbonyl}-2(1H)-quinazolinone;
(af) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-7-diethylaminocarbonyl-3,4-dihydro-2(1H)-quinazolinone;
(ag) trans-7-aminocarbonyl-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone;
(ah) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-7-{[(hydroxycarbonylmethyl)amino]carbonyl}-2(1H)-quinazolinone;
and
(ai) trans-1-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-2,4-dihydro-5-phenyl-3(3H)1,2,4-triazolone,
or a salt thereof.

34 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/169,078Filed 27 Jun 2005 · continuation
Priority: DE 199 52 14729 Oct 1999
Published: US 2005/0267137 A11 Dec 2005
Granted: 5 Aug 2008
Term ends: Not estimatedThe source records don’t support an estimate.

Classification15 codes

C07D 401/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 5/24
Drugs for disorders of the endocrine system: of the sex hormones
A61P 9/00
Drugs for disorders of the cardiovascular system

Family

PCT/EP00/10391Parent of this continuation · filed 29 Oct 1999
Application10/121,872Parent of this continuation · filed 12 Apr 2002
US 2005/0267137 A1Pre-grant publication · published 1 Dec 2005
US 2003/0139417 A1Published application
US 7,407,963 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of general formula (I)

wherein:
R is a saturated or mono- or diunsaturated 5- to 7-membered aza, diaza, triaza, oxaza, thiaza, thiadiaza, or S,S-dioxido-thiadiaza heterocyclic group linked via a carbon or nitrogen atom, and
wherein the heterocyclic group of R:
(i) optionally contains one or two carbonyl groups adjacent to a nitrogen atom thereof,
(ii) is optionally substituted by an alkyl group at one of the nitrogen atoms, and
(iii) is optionally substituted at one or two carbon atoms thereof by identical or different substituent groups selected from:
(a) a straight-chain or branched alkyl group, or a phenyl, phenylmethyl, naphthyl, biphenylyl group, or
(b) a pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl, or 1-methylimidazolyl group,
wherein an olefinic double bond thereof is optionally fused with a benzene, pyridine, diazine, 1,3-oxazole, thiophene, furan, thiazole, pyrrole, N-methylpyrrole, quinoline, imidazole, or N-methylimidazole ring, and
wherein the phenyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl, or 1-methylimidazolyl groups contained in R and the benzo, thieno, pyrido- and diazino-fused heterocyclic groups in R are optionally independently additionally mono-, di-, or trisubstituted by:
(a) a fluorine, chlorine, or bromine atom,
(b) an alkyl, dialkylaminoalkoxy, nitro, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, phenyl, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkoxy, hydroxycarbonylalkoxy, carboxy, carboxyalkyl, dialkyl-aminoalkyl, hydroxy, amino, acetylamino, propionylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, [N-alkyl-N-(dialkylaminoalkyl)amino]carbonyl, [(hydroxycarbonylalkyl)amino]carbonyl, [(alkoxycarbonylalkyl)amino]carbonyl, (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, trifluoromethylsulfonyl, or C3-C8 cycloalkyl group,
(c) a 4- to 8-membered alkyleneimino group wherein a methylene group in the 3-, 4-, or 5-position is optionally replaced by an oxygen atom or a methylimino group, or
(d) an alkoxy group optionally substituted in the ω-position by a 5- to 7-membered heteroalicyclic group that is linked via a carbon or nitrogen atom and contains one or two heteroatoms not directly connected to each other selected from oxygen and nitrogen,
wherein multiple substitution of the aforementioned phenyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl, or 1-methylimidazolyl groups contained in R and the benzo, thieno, pyrido- and diazino-fused heterocyclic groups in R by phenyl, C3-C8 cycloalkyl or 4- to 8-membered alkyleneimino groups is excluded;
and
R1 is a phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-formyl-1H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl, 1H-indazol-3-yl, 1-methyl-1H-indazol-3-yl, benzo[b]fur-3-yl, benzo[b]thien-3-yl, pyridinyl, quinolinyl, or isoquinolinyl group,
wherein each group of R1 is optionally independently mono-, di-, or trisubstituted by a substituent group selected from:
(a) a fluorine, chlorine, or bromine atom,
(b) a branched or unbranched alkyl, C3-C8 cycloalkyl, phenylalkyl, alkenyl, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonyl, carboxy, dialkylaminoalkyl, dialkylaminoalkoxy, nitro, hydroxy, amino, acetylamino, propionylamino, methylsulfonyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl, cyano, tetrazolyl, phenyl, pyridinyl, thiazolyl, furyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl, or trifluoromethylsulfonyl group,
wherein the hydroxy, amino, indolyl and imidazolyl groups contained in the abovementioned groups are each optionally independently substituted by a protecting group selected from:
(a) a phenylalkoxycarbonyl group with 1 to 3 carbon atoms in the alkoxy moiety optionally substituted in the phenyl nucleus by a halogen atom, a nitro or phenyl group, or one or two methoxy groups,
(b) an alkoxycarbonyl group having a total of 1 to 5 carbon atoms in the alkyl moiety, or
(c) a formyl, acetyl, trifluoroacetyl, allyloxycarbonyl, 2,2,2-trichloro-(1,1-dimethylethoxy)carbonyl, or 9-fluorenylmethoxycarbonyl group,
wherein all the abovementioned alkyl and alkoxy groups and the alkyl or alkylene moieties present within the other groups specified contain 1 to 5 carbon atoms, unless otherwise stated,
or a diastereomer, enantiomer, or salt thereof.

23 more elements

Facts

Application

11/169,078Filed 27 Jun 2005 · continuation

Priority

DE 199 52 14729 Oct 1999

Published

US 2005/0267137 A11 Dec 2005

Granted

5 Aug 2008

Term ends

Not estimatedThe source records don’t support an estimate.

Classification15 codes

C07D 401/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 5/24
Drugs for disorders of the endocrine system: of the sex hormones
A61P 9/00
Drugs for disorders of the cardiovascular system

Family

PCT/EP00/10391Parent of this continuation · filed 29 Oct 1999

Application10/121,872Parent of this continuation · filed 12 Apr 2002

US 2005/0267137 A1Pre-grant publication · published 1 Dec 2005

US 2003/0139417 A1Published application

US 7,407,963 B2This patent

From the US filing history. Foreign family members aren’t listed.