# US 8,569,313 B2 · Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors

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- Number: US 8,569,313 B2
- Document ID: US8569313B2
- Status: Granted
- Kind: B2
- Application number: 12/529,767
- Filed: 2008-03-05
- Published: 2010-12-02
- Granted: 2013-10-29
- Earliest claimed: 2007-03-06
- Assignees: The Medicines Company (Leipzig) GmbH
- Applicants: Torsten Steinmetzer; Andrea Schweinitz; Daniel Donnecke
- Inventors: Torsten Steinmetzer; Andrea Schweinitz; Daniel Donnecke
- Web page: https://patentgrep.com/patent/US8569313B2

## CPC

- C07D 211/08: with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- C07D 211/26: with hydrocarbon radicals, substituted by nitrogen atoms
- C07D 211/34: with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 211/60: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 295/16: acylated on ring nitrogen atoms
- C07D 295/18: by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D 295/20: by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

The compound according to the claim 1, wherein
R2′ is not present;
R1 is selected from the group consisting of a singly or multiply substituted phenyl residue, pyridyl residue, pyrimidine residue, indole residue, tetrahydropyridyl residue, piperidinon residue and pyridazinone residue; and
R2 is:
(i) a straight chain aminoalkyl residue having 1-6 carbon atoms, or
(ii) —(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 and R2 are:
(i) each independently a straight chain aminoalkyl residue having 1 to 6 carbon atoms, or
(ii) R1 is an unramified n-amino butyl residue and R2 is a straight chain aminoalkyl residue having 1 to 6 carbon atoms;
or
R1 is a H2N—(CH2)n—C(═O)—NH-residue where n equals a whole number from 1 to 4; and
R2 is:
(i) —(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
(ii) —(CH2)o—C(═O)—OR5 where o is a whole number from 1 to 6, and R5 is a hydrogen or a straight chain alkyl group with 1 to 4 carbon atoms;
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.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein R2 is in the meta or para position.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein R2 is in the para position and R2′ in the ortho or meta position.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein R1 is a ring structure substituted in the meta position, the para position, or both the meta and para positions.

### Claim 6 (depends on 5)

The compound according to claim 5, wherein each substitution of R1 is independently selected from the group consisting of: R6—O—, where R6 is a ramified or straight chain alkyl residue with 1 to 6 carbon atoms; (CH3)—(CH2)p—, where p equals a whole number from 0 to 6; a halogen; chlorine; and an amino group.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein R1 is a phenyl residue substituted in the meta position, the para position, or both the meta and para positions, and wherein each substitution is independently selected from the group consisting of: R6—O—, where R6 is a ramified or straight chain alkyl residue with 1 to 6 carbon atoms; (CH3)—(CH2)p— where p equals a whole number from 0 to 6; a halogen; and chlorine.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein R1 is a pyridyl residue, a pyrimidine residue or a tetrahydropyridyl residue, wherein the residue is substituted in the meta position, the para position, or both the meta and para positions, and wherein each substitution is independently selected from the following residues: (CH3)—(CH2)p— where p equals a whole number from 0 to 6; and an amino group.

### Claim 9 (depends on 8)

The compound according to claim 8, wherein R1 is a pyridyl residue substituted with an amino group or a tetrahydropyridyl residue substituted with an amino group.

### Claim 10 (depends on 8)

The compound according to claim 8, wherein R1 is a pyrimidine residue substituted with a (CH3)—(CH2)p-group where p equals a whole number from 0 to 6.

### Claim 11 (depends on 1)

The compound according to claim 1, wherein a polyethyleneglycol chain is covalently coupled to the compound by a linker.

### Claim 12 (depends on 1)

The compound according to claim 1, wherein amino acids present as central structure motifs in the formulas (I), (II) and (III) are in the L-configuration.

### Claim 13

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.

### Claim 14 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1.

### Claim 15 (depends on 14)

A method for inhibiting or treating tumor metastasis in a subject, comprising administering a pharmaceutical composition of claim 14 to a subject having a tumor, thereby inhibiting or treating tumor metastasis.

### Claim 16 (depends on 14)

A method for inhibiting of matriptase in a subject, comprising administering a pharmaceutical composition of claim 14 to a subject, thereby inhibiting matriptase.

### Claim 17 (depends on 1)

An in vitro method for inhibiting matriptase, comprising contacting a cell expressing matriptase with a compound of claim 1, thereby inhibiting matriptase.

### Claim 18 (depends on 13)

A pharmaceutical composition comprising a compound of claim 13.

### Claim 19 (depends on 18)

A method for treating tumor metastasis in a subject, comprising administering a pharmaceutical composition of claim 18 to a subject having a tumor, thereby treating tumor metastasis.

### Claim 20 (depends on 18)

A method for inhibiting matriptase in a subject, comprising administering a pharmaceutical composition of claim 18 to a subject, thereby inhibiting matriptase.

### Claim 21 (depends on 18)

An in vitro method for inhibiting matriptase, comprising contacting a cell expressing matriptase with a compound of claim 18, thereby inhibiting matriptase.