US 8,569,313 B2Granted

Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors

AssigneeThe Medicines Company (Leipzig) GmbH

InventorsTorsten Steinmetzer, Andrea Schweinitz, Daniel Donnecke

Life of this patent

Estimating the term…

Abstract

The invention relates to meta-substituted phenyl sulfonyl amides of secondary amino acid amides according to the general formula (I), (II), or (III), the production thereof, and the use thereof as matriptase inhibitors, in particular the use thereof as drugs for inhibiting tumor growth and/or metastasization.

Claims21

Dependent claims

A compound according to the formula (I)

or a salt thereof, wherein
R1 is a singly or multiply substituted ring structure selected from:
(i) an aryl residue, which may be partially or wholly hydrogenated,
(ii) a heteroaryl residue, which may be partially or wholly hydrogenated,
(iii) a non-hydrogenated aryl residue,
(iv) a non-hydrogenated heteroaryl residue,
(v) a heteroaryl residue with one or two nitrogen atoms,
(vi) a phenyl residue,
(vii) a pyridyl residue,
(viii) a pyrimidine residue,
(ix) an indole residue,
(x) a tetrahydropyridyl residue,
(xi) a piperidinon residue, or
(xii) a pyridazinone residue;
and
R2 and R2′ are each independently:
(i) a ramified or straight chain alkyl residue having 1-6 carbon atoms, wherein one or more methylene groups may be replaced by oxygen or nitrogen,
(ii) a ramified or straight chain amino alkyl residue having 1-6 carbon atoms,
(iii) a ramified or straight chain guanidine alkyl residue having 1-6 carbon atoms,
(iv) —(CH2)m—C(═O)—NHR4 where m equals a whole number from 0 to 4 and R4 is a hydrogen or a —(CH2)k—CH3 residue where k equals a whole number from 0 to 3, or
(v) R2 and R2′ together form a ring structure with the piperidide selected from the group consisting of:
or
R1 is:
(i) a ramified or straight chain hydroxy alkyl residue having 1 to 6 carbon atoms,
(ii) a straight chain aminoalkyl residue,
(iii) a 3-azetidin-C(═O)—NH-residue, or
(iv) an unramified n-amino butyl residue;
and
R2 and R2′ are each independently:
(i) a ramified or straight chain aminoalkyl residue having 1-6 carbon atoms,
(ii) a ramified or straight chain guanidino alkyl residue having 1-6 carbon atoms,
(iii) a straight chain amino ethyl residue, or
(iv) R2 is —(CH2)m—C(═O)—NHR4 where m equals a whole number from 0 to 4, and R4 is a hydrogen or a —(CH2)k—CH3 residue where k equals a whole number from 0 to 3;
or
R1 is:
(i) a H2N—(CH2)n—C(═O)—NH-residue where n equals a whole number from 1 to 4,
(ii) a HO—(CH2)n—C(═O)—NH-residue where n equals a whole number from 1 to 4, or
(iii) a 3-azetidin-C(═O)—NH-residue;
and
R2 and R2′ are:
(i) each independently a non-basic residue,
(ii) R2 is —(CH2)m—C(═O)—NHR4 where m equals a whole number from 0 to 4, and R4 is a hydrogen or a —(CH2)k—CH3 residue where k equals a whole number from 0 to 3, and R2′ is a non-basic residue,
(iii) R2 is —(CH2)o—C(═O)—OR5 where o is a whole number from 1 to 6 and R5 is a hydrogen or a ramified or straight chain alkyl group with 1 to 4 carbon atoms, and R2′ is a non-basic residue, or
(iv) R2 and R2′ together form a ring structure with the piperidide selected from the group consisting of:
and
R3 is selected from the group consisting of a hydrogen, a hydroxyl group, an alkoxy group, an acetyloxy group and an alkyloxycarbonyl group, whereby the alkyl residue contains 1-6 carbon atoms.

43 more elements

A compound selected from the group consisting of:

3-(3,4-dimethoxyphenyl)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(2-amino ethyl)piperidide,
3-(phenyl)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(2-amino ethyl)piperidide,
3-(4-methoxyphenyl)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(2amino ehtyl)piperidide,
3-(4-ethoxyphenyl)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(2amino ehtyl)piperidide,
3-(4-ethylphenyl)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(2-amino ethyl)piperidide,
3-(4-isopropoxyphenyl)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(2-amino ethyl)piperidide,
3-(4-chlorphenyl)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(2-Amino ethyl)piperidide,
3-(3-chlorphenyl)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(2-Amino ethyl)piperidide,
3-(2-chlorphenyl)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(2-Amino ethyl)piperidide,
3-(4-pyridyl)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(2-amino ethyl)piperidide,
3-(3-pyridyl)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(2-amino ethyl)piperidide,
3-(2-methyl-4-pyrimidinyl)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(2-amino ethyl)piperidide,
3-(5-indolyl)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(2-amino ethyl)piperidide,
3-(4-amino-3-pyridyl)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(2-amino ethyl)piperidide,
3-(4-amino-3-tetrahydropyridyl)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(2-amino ethyl)piperidide,
3-(1-amino butyl)-phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(2-amino ethyl)piperidide,
3-(H-β-alanyl-NH)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(methylamido buteryl)piperidide,
3-(4-ethoxyphenyl)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(methylamido buteryl)piperidide,
3-(4-ethylphenyl)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(methylamido buteryl)piperidide,
3-(H-β-alanyl-NH)phenyl sulfonyl-L-phenylalanine (3-amidino)-4-piperidinbuteryl-O-methylat,
3-(H-β-alanyl-NH)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(amido buteryl)piperidide,
3-(H-β-alanyl-NH)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(buteryl)piperidide,
3-(H-β-alanyl-NH)phenyl sulfonyl-L-phenylalanine(3-amidino)-isonipecotylamide,
3-(H-β-alanyl-NH)phenyl sulfonyl-L-phenylalanine(3-amidino)-nipecotyl amide,
3-(H-β-alanyl-NH)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(ethyloxycarbonyl) piperazid,
3-(H-β-alanyl-NH)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-benzyloxycarbonyl) piperazid,
3-(H-β-alanyl-NH)phenyl sulfonyl-L-phenylalanine(3-amidino)-piperazid,
3-(H-β-alanyl-NH)phenyl sulfonyl-L-phenylalanine(3-amidino)-piperidide,
3-(pyridazinone)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(methylamido buteryl) piperidide,
3-(piperidinon)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(methylamido buteryl) piperidide,
3-(piperazinone)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(methylamido buteryl) piperidide,
3-(4-ethoxyphenyl)phenyl sulfonyl-L-phenylalanine(3-hydroxyamidino)-piperidine buteryl-N-methylamide,
3-(4-ethylphenyl)phenyl sulfonyl-L-phenylalanine(3-hydroxyamidino)-piperidine buteryl-N-methylamide,
3-(H-βalanine-NH)phenyl sulfonyl-L-phenylalanine(3-aminomethyl)-4-(2-amino ethyl) piperidide,
3-(4-methoxyphenyl)phenyl sulfonyl-L-phenylalanine(3-aminomethyl)-4-(2-amino ethyl)piperidide,
3-(H-β-alanyl-NH)phenyl sulfonyl-L-phenylalanine(3-aminomethyl)-4-(benzyloxycarbonyl)piperazid,
3-(1-hydroxybutyl)-phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(2-amino ethyl) piperidide,
3-(3-azetidin-CONH)-phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(methylamido buteryl)piperidide,
3-(3-azetidin-CONH)-phenyl sulfonyl-L-phenylalanine(3-hydroxyamidino)-4-(methylamido buteryl)piperidide,
3-(3-azetidin-CONH)-phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(2-amino ethyl)piperidide,
3-(4-tert-butylphenyl)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(methylamido buteryl)piperidide,
3-(4-tert-butylphenyl)phenyl sulfonyl-L-phenylalanine(3-hydroxyamidino)-4-(methylamido buteryl)piperidide,
3-(4-tert-butylphenyl)phenyl sulfonyl-L-phenylalanine(3-methoxyamidino)-4-(methylamido buteryl)piperidide,
3-(4-isopropylphenyl)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(methylamido buteryl)piperidide,
3-(4-methoxy-3-pyridyl)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(methylamido buteryl)piperidide,
3-(4-amino-3-pyridyl)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(methylamido buteryl)piperidide,
3-(4-amino-3-tetrahydropyridyl)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(methylamido buteryl)piperidide,
3-(Nα-(CH3-PEG10000-CH2-CH2-CO)-α,β-diaminopropionyl-NH)phenyl sulfonyl-L-phenylalanine (3-amidino)-4-(2-amino ethyl)-piperidide,
3-(H-β-alanyl-NH)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(CH3-PEG10000-CH2-CH2-amido buteryl)piperidide,
3-(CH3-PEG10000-CH2-CH2-CO)-β-Ala-NH)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(2-amino ethyl)-piperidide,
3-(H-β-alanyl-NH)phenyl sulfonyl-L-phenylalanine(3-amidino)-4-(CH3-PEG10000-CH2-CH2-NH-Suc)piperazid, and
3-(H-β-alanyl-NH)phenyl sulfonyl-L-phenylalanine(3-amidino)-nipecotyl-benzyl ester.

49 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/529,767Filed 5 Mar 2008
Priority: DE 10 2007 010 8156 Mar 2007
Published: US 2010/0305090 A12 Dec 2010
Granted: 29 Oct 2013
Term ends: Not estimatedThe source records don’t support an estimate.

Classification12 codes

C07D 211/08
Having no double bonds between ring members or between ring members and non-ring members: with hydrocarbon or substituted hydrocarbon radicals…
A61P 35/00
Antineoplastic agents
A61P 35/04
Antineoplastic agents: specific for metastasis
C07D 211/26
With substituted hydrocarbon radicals attached to ring carbon atoms: with hydrocarbon radicals, substituted by nitrogen atoms

Family

US 2010/0305090 A1Pre-grant publication · published 2 Dec 2010
US 8,569,313 B2This patent

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

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Abstract

A compound according to the formula (I)

or a salt thereof, wherein
R1 is a singly or multiply substituted ring structure selected from:
(i) an aryl residue, which may be partially or wholly hydrogenated,
(ii) a heteroaryl residue, which may be partially or wholly hydrogenated,
(iii) a non-hydrogenated aryl residue,
(iv) a non-hydrogenated heteroaryl residue,
(v) a heteroaryl residue with one or two nitrogen atoms,
(vi) a phenyl residue,
(vii) a pyridyl residue,
(viii) a pyrimidine residue,
(ix) an indole residue,
(x) a tetrahydropyridyl residue,
(xi) a piperidinon residue, or
(xii) a pyridazinone residue;
and
R2 and R2′ are each independently:
(i) a ramified or straight chain alkyl residue having 1-6 carbon atoms, wherein one or more methylene groups may be replaced by oxygen or nitrogen,
(ii) a ramified or straight chain amino alkyl residue having 1-6 carbon atoms,
(iii) a ramified or straight chain guanidine alkyl residue having 1-6 carbon atoms,
(iv) —(CH2)m—C(═O)—NHR4 where m equals a whole number from 0 to 4 and R4 is a hydrogen or a —(CH2)k—CH3 residue where k equals a whole number from 0 to 3, or
(v) R2 and R2′ together form a ring structure with the piperidide selected from the group consisting of:
or
R1 is:
(i) a ramified or straight chain hydroxy alkyl residue having 1 to 6 carbon atoms,
(ii) a straight chain aminoalkyl residue,
(iii) a 3-azetidin-C(═O)—NH-residue, or
(iv) an unramified n-amino butyl residue;
and
R2 and R2′ are each independently:
(i) a ramified or straight chain aminoalkyl residue having 1-6 carbon atoms,
(ii) a ramified or straight chain guanidino alkyl residue having 1-6 carbon atoms,
(iii) a straight chain amino ethyl residue, or
(iv) R2 is —(CH2)m—C(═O)—NHR4 where m equals a whole number from 0 to 4, and R4 is a hydrogen or a —(CH2)k—CH3 residue where k equals a whole number from 0 to 3;
or
R1 is:
(i) a H2N—(CH2)n—C(═O)—NH-residue where n equals a whole number from 1 to 4,
(ii) a HO—(CH2)n—C(═O)—NH-residue where n equals a whole number from 1 to 4, or
(iii) a 3-azetidin-C(═O)—NH-residue;
and
R2 and R2′ are:
(i) each independently a non-basic residue,
(ii) R2 is —(CH2)m—C(═O)—NHR4 where m equals a whole number from 0 to 4, and R4 is a hydrogen or a —(CH2)k—CH3 residue where k equals a whole number from 0 to 3, and R2′ is a non-basic residue,
(iii) R2 is —(CH2)o—C(═O)—OR5 where o is a whole number from 1 to 6 and R5 is a hydrogen or a ramified or straight chain alkyl group with 1 to 4 carbon atoms, and R2′ is a non-basic residue, or
(iv) R2 and R2′ together form a ring structure with the piperidide selected from the group consisting of:
and
R3 is selected from the group consisting of a hydrogen, a hydroxyl group, an alkoxy group, an acetyloxy group and an alkyloxycarbonyl group, whereby the alkyl residue contains 1-6 carbon atoms.

43 more elements

Facts

Application

12/529,767Filed 5 Mar 2008

Priority

DE 10 2007 010 8156 Mar 2007

Published

US 2010/0305090 A12 Dec 2010

Granted

29 Oct 2013

Term ends

Not estimatedThe source records don’t support an estimate.

Classification12 codes

C07D 211/08
Having no double bonds between ring members or between ring members and non-ring members: with hydrocarbon or substituted hydrocarbon radicals…
A61P 35/00
Antineoplastic agents
A61P 35/04
Antineoplastic agents: specific for metastasis
C07D 211/26
With substituted hydrocarbon radicals attached to ring carbon atoms: with hydrocarbon radicals, substituted by nitrogen atoms