# US 8,541,573 B2 · Substituted sulfonamide compounds

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- Number: US 8,541,573 B2
- Document ID: US8541573B2
- Status: Granted
- Kind: B2
- Application number: 12/397,771
- Filed: 2009-03-04
- Published: 2009-12-03
- Granted: 2013-09-24
- Earliest claimed: 2008-03-05
- Assignees: Gruenenthal GmbH
- Applicants: Stefan Oberboersch; Ruth Jostock; Klaus Schiene; Jean De Vry; Tieno Germann; Sabine Hees; Stefan Schunk; Melanie Reich
- Inventors: Stefan Oberboersch; Ruth Jostock; Klaus Schiene; Jean De Vry; Tieno Germann; Sabine Hees; Stefan Schunk; Melanie Reich
- Web page: https://patentgrep.com/patent/US8541573B2

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/06: Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/14: Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 17/00: Drugs for dermatological disorders
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/06: Antimigraine agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 35/00: Antineoplastic agents
- C07D 211/58: attached in position 4
- C07D 401/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Substituted sulfonamide compounds corresponding to the formula I processes for the preparation thereof, pharmaceutical compositions containing these compounds and the use of substituted sulfonamide compounds for the preparation of pharmaceutical compositions for treating pain and other conditions at least partly mediated via the bradykinin 1 receptor.

## Claims

### Claim 1

A substituted sulfonamide compound corresponding to formula I:
wherein
n represents 0, 1 or 2;
o represents 1, 2 or 3;
p represents 1 or 2;
q represents 0 or 1;
r represents 0 or 1;
the sum of p+q+r equals 3;
Q represents a single bond, —O— or —CH2—;
R1 represents aryl or heteroaryl or denotes an aryl or heteroaryl bonded via a C1-3-alkylene group;
R2 represents H, C1-6-alkyl, C3-8cycloalkyl, aryl or heteroaryl; or denotes a C3-8-cycloalkyl, aryl or heteroaryl bonded via a C1-6-alkylene group, C2-6-alkenylene group or C2-6-alkynylene group; and
R3 represents H, C1-6-alkyl, aryl or heteroaryl; or denotes an aryl or heteroaryl bonded via a C1-6-alkylene group, C2-6-alkenylene group or C2-6-alkynylene group; or
R2 and R3 together form a heterocyclic ring, which optionally may be fused with an aryl or heteroaryl ring,
wherein said heterocyclic ring may be saturated or mono- or polyunsaturated, but not aromatic, is 4-, 5-, 6- or 7-membered, and may contain in addition to the N hetero atom to which R2 is bonded, at least one further hetero atom or group selected from the group consisting of N, NR12, O, S, S═O and S(═O)2;
wherein R12 represents H, C1-6-alkyl, —C(═O)—R13, C3-8-cycloalkyl, aryl, heteroaryl or a C3-8-cycloalkyl, aryl or heteroaryl bonded via a C1-3-alkylene group, and R13 denotes C1-6-alkyl, C3-8-cycloalkyl, aryl, heteroaryl or a C3-8-cycloalkyl, aryl or heteroaryl bonded via a C1-3-alkylene group,
R4 and R5 each independently represent H, C1-6-alkenyl, C2-6-alkynyl, C3-8-cycloalkyl, 3- to 8-membered heterocycloalkyl, aryl or heteroaryl or a C3-8-cycloalkyl, 3- to 8-membered heterocycloalkyl, aryl or heteroaryl bonded via a C1-3-alkylene group; or
R4 and R5 together form an unsubstituted or mono- or polysubstituted heterocyclic ring, which optionally may be fused with a saturated or mono- or polyunsaturated or aromatic, unsubstituted or mono- or polysubstituted ring system,
wherein said heterocyclic ring may be saturated or mono- or polyunsaturated but not aromatic, is 4-, 5-, 6- or 7-membered, and may contain in addition to the N hetero atom to which R4 and R5 are bound, at least one hetero atom or group selected from the group consisting of N, NR8, O, S, S═O and S(═O)2, wherein R8 represents a moiety selected from the group consisting of H, C1-6-alkyl, C3-8-cycloalkyl, aryl, heteroaryl, and aryl, or denotes heteroaryl or C3-8-cycloalkyl bonded via a C1-3-alkylene group, and
wherein said ring system is 4-, 5-, 6- or 7-membered, and optionally may contain at least one hetero atom or group selected from the group consisting of N, NR17, O, S, S═O and S(═O)2, wherein R17 represents a moiety selected from the group consisting of H, C1-6-alkyl, C3-8-cycloalkyl, aryl, heteroaryl and aryl, or denotes heteroaryl or C3-8-cycloalkyl bonded via a C1-3-alkylene group;
R6 represents H, C1-6-alkyl, or aryl, or denotes a C3-8cycloalkyl bonded via a C1-3-alkylene group, an aryl bonded via a C1-3-alkylene group or a heteroaryl bonded via a C1-3-alkylene group, and
R7 represents C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl, C3-8cycloalkyl, aryl or heteroaryl; or denotes a C3-8-cycloalkyl, aryl or heteroaryl bonded via a C1-6-alkylene group; or
R6 and R7 together with the —N—C(═O) group form a ring of the type
wherein d represents 0 or 1 and R14 and R15 together represent an annellated unsubstituted or substituted aryl or heteroaryl group;
wherein said C1-6-alkyl, C1-6-alkylene, C2-6-alkenylene, C2-6-alkynylene, C3-8-cycloalkyl, C3-8-heterocycloalkyl, aryl and heteroaryl groups each optionally may be unsubstituted or substituted one or more times by identical or different substituents; and said C1-6-alkyl, C1-6-alkylene, C2-6-alkenylene and C2-6-alkynylene groups each may be branched or unbranched;
or a physiologically acceptable salt thereof.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein said compound is in the form of an isolated stereoisomer.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein said compound is in the form of a mixture of stereoisomers in any mixing ratio.

### Claim 4 (depends on 3)

A compound according to claim 3, wherein said mixture is a racemic mixture.

### Claim 5 (depends on 1)

A compound according to claim 1, wherein n represents 0 or 1.

### Claim 6 (depends on 1)

A compound according to claim 1, wherein R1 represents a phenyl, naphthyl, indolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzoxadiazolyl, pyrrolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazothiazolyl, carbazolyl, dibenzofuranyl, dibenzothiophenyl, benzyl or 2-phenethyl group, wherein said group optionally may be unsubstituted or substituted one or more times by identical or different substituents selected from the group consisting of —O—C1-3-alkyl, C1-6-alkyl, F, Cl, Br, I, CF3, OCF3, OH, SH, phenyl, naphthyl, furyl, thienyl and pyridinyl.

### Claim 7 (depends on 6)

A compound according to claim 6, wherein R1 represents an unsubstituted or optionally mono- or polysubstituted group selected from the group consisting of phenyl, naphthyl, benzothiophenyl, benzoxadiazolyl, thiophenyl, pyridinyl, imidazothiazolyl or dibenzofuranyl.

### Claim 8 (depends on 1)

A compound according to claim 1, wherein p, q and r each represent 1.

### Claim 9 (depends on 1)

A compound according to claim 1, wherein
Q represents a single bond, CH2 or —O—;
n represents 0 or 1; and
o represents 1.

### Claim 10 (depends on 1)

A compound according to claim 1, wherein R4 and R5 each independently represent H or substituted or unsubstituted C1-C6-alkyl, or the group —NR4R5 represents a heterocylic ring corresponding to formula IIa:
wherein
X represents O, S, NR8 or C(halogen)2; wherein R8 represents H; C1-6-alkyl; aryl, or heteroaryl, or denotes an aryl or heteroaryl group bonded via a C1-3-alkylene group;
s represents 0, 1 or 2, with the proviso that s is not 0 if X is NR8; and
said C1-6-alkyl, C1-3-alkylene, aryl and heteroaryl groups each optionally may be unsubstituted or substituted one or more times by identical or different substituents.

### Claim 11 (depends on 10)

A compound according to claim 10, wherein X represents NR8; wherein:
R8 represents H; C1-6-alkyl, phenyl, naphthyl, or a 5- to 6-membered heteroaryl containing 1 or 2 N atoms, or denotes a phenyl, naphthyl or 5- to 6-membered heteroaryl containing 1 or 2 N atoms bonded via a C1-3-alkylene group; and
s represents 1.

### Claim 12 (depends on 1)

A compound according to claim 1, wherein R6 represents H, C1-6-alkyl, or aryl, or denotes aryl bonded via a C1-3-alkylene group; wherein said C1-6-alkyl, C1-3-alkylene and aryl groups each may be unsubstituted or substituted once or more times by identical or different substituents.

### Claim 13 (depends on 1)

A compound according to claim 1, wherein R7 represents C1-6-alkyl; C4-7-cycloalkyl; aryl; a 5- to 6-membered heteroaryl containing 1 to 3 hetero atoms selected from the group consisting of N, O and S; or a C4-6-cycloalkyl, aryl, or 5- to 6-membered heteroaryl containing 1 to 3 hetero atoms selected from the group consisting of N, O and S bonded via a C1-3-alkylene group;
wherein said C1-6-alkyl, C4-7-cycloalkyl, aryl and heteroaryl each may be unsubstituted or substituted one or more times by identical or different substituents.

### Claim 14 (depends on 13)

A compound according to claim 13, wherein R7 represents C1-6-alkyl; cyclopentyl; cyclohexyl; phenyl; naphthyl; pyridinyl; or a cyclopentyl, cyclohexyl, phenyl, naphthyl or pyridinyl bonded via a C1-3-alkylene group.

### Claim 15 (depends on 1)

A compound according to claim 1, wherein R2 represents H, C1-6alkyl, C3-8-cycloalkyl or aryl; or denotes a C3-6-cycloalkyl or aryl bonded via a C1-6-alkylene group, C2-6-alkenylene group or C2-6-alkynylene group; wherein said C1-6-alkyl, C3-6-cycloalkyl, C2-6-alkylene, C2-6-alkenylene, C2-6-alkynylene, and aryl each may be unsubstituted or substituted one or more times by identical or different substituents selected from the group consisting of C1-6-alkyl, C1-6-alkyl-O—, F, Cl, Br, I, CF3, OCF3, OH and SH.

### Claim 16 (depends on 1)

A compound according to claim 1, wherein R3 represents H, C1-6-alkyl or aryl; or denotes an aryl bonded via a C1-6-alkylene group, C2-6-alkenylene group or C2-6-alkynylene group, wherein said C1-6-alkyl, C2-6-alkylene, C2-6-alkenylene, C2-6-alkynylene, and aryl each may be unsubstituted or substituted one or more times by identical or different substituents selected from the group consisting of C1-6-alkyl, C1-6-alkyl-O—, F, Cl, Br, I, CF3, OCF3, OH and SH.

### Claim 17 (depends on 1)

A compound according to claim 1, corresponding to formula Ia:
wherein
a, b and c each independently represent 0 or 1;
R9, R10, R11a, R11b and R11c each independently represent H or two vicinal radicals from R9, R10, R11a, R11b and R11c form a 5- or 6-membered annellated aryl or heteroaryl ring, which optionally may be unsubstituted or substituted one or more times by identical or different substituents; and
R1, R4, R5, R6 and R7 and Q, n, o, p, q and r each have the meanings given in claim 1.

### Claim 18 (depends on 17)

A compound according to claim 17, corresponding to formula Ib:
wherein
R9, R10, R11a and R11b each independently represent H or two vicinal radicals from R9, R10, R11a, R11b and R11c form a 5- or 6-membered aromatic or heteroaromatic ring, which may be unsubstituted or substituted one or more times with substituents independently selected from the group consisting of methyl, methoxy, CF3, F, Cl and Br; and
R1, R4, R5, R6 and R7 and Q, n and o each have the meanings given in claim 17.

### Claim 19 (depends on 1)

A compound according to claim 1, selected from the group consisting of
(1) N-((1-(2-(2-(4-methoxy-N,2,6-trimethylphenylsulfonamido)ethoxy)acetyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)isonicotinamide;
(2) N-((1-(3-(1-(4-chloro-2,5-dimethylphenylsulfonyl)piperidin-2-yl)propanoyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)acetamide;
(3) N-((1-(2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)-2-phenylacetamide;
(4) N-((4-(4-methylpiperazin-1-yl)-1-(2-(1-(3-(trifluoromethyl)phenylsulfonyl)-piperidin-2-yl)acetyl)piperidin-4-yl)methyl)-2-phenylacetamide;
(5) N-((1-(2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)-benzamide;
(6) N-((1-(3-(1-(4-chloro-2,5-dimethylphenylsulfonyl)piperidin-2-yl)propanoyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)benzamide;
(7) N-((1-(2-((1-(3,4-dichlorophenylsulfonyl)-1,2,3,4-tetrahydroquinolin-2-yl)methoxy)acetyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)-acetamide;
(8) N-((4-(4-methylpiperazin-1-yl)-1-(3-(naphthalene-2-sulfonamido)-3-phenylpropanoyl)piperidin-4-yl)methyl)-2-phenylacetamide;
(9) N-((1-(3-(1-(4-chloro-2,5-dimethylphenylsulfonyl)piperidin-2-yl)propan-oyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)picolinamide,
(10) N-((1-(3-(1-(4-chloro-2,5-dimethylphenylsulfonyl)piperidin-2-yl)-propanoyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)-2-phenylacetamide;
(11) N-((1-(3-(1-(4-chloro-2,5-dimethylphenylsulfonyl)piperidin-2-yl)propan-oyl)-4-(4-(pyridin-4-yl)piperazin-1-yl)piperidin-4-yl)methyl)acetamide,
(12) N-((4-(4-methylpiperazin-1-yl)-1-(2-(1-(3-(trifluoromethyl)phenylsulfonyl)-piperidin-2-yl)acetyl)piperidin-4-yl)methyl)acetamide;
(13) N-((1-(2-((1-(3,4-dichlorophenylsulfonyl)-1,2,3,4-tetrahydroquinolin-2-yl)methoxy)acetyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)-2-phenylacetamide;
(14) N-((1-(3-(naphthalene-2-sulfonamido)-3-phenylpropanoyl)-4-(4-(pyridin-4-yl)piperazin-1-yl)piperidin-4-yl)methyl)acetamide;
(15) N-((1-(2-(2-(4-methoxy-N,2,6-trimethylphenylsulfonamido)ethoxy)acetyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)-2-phenylacetamide;
(16) N-((4-(4-methylpiperazin-1-yl)-1-(3-(naphthalene-2-sulfonamido)-3-phenylpropanoyl)piperidin-4-yl)methyl)benzamide;
(17) N-((1-(2-((1-(3,4-dichlorophenylsulfonyl)-1,2,3,4-tetrahydroquinolin-2-yl)-methoxy)acetyl)-4-(4-(pyridin-4-yl)piperazin-1-yl)piperidin-4-yl)methyl)-acetamide;
(18) N-((4-(4-methylpiperazin-1-yl)-1-(2-(1-(3-(trifluoromethyl)phenylsulfonyl)-piperidin-2-yl)acetyl)piperidin-4-yl)methyl)picolinamide;
(19) N-((4-(4-methylpiperazin-1-yl)-1-(3-(naphthalene-2-sulfonamido)-3-phenylpropanoyl)piperidin-4-yl)methyl)picolinamide;
(20) N-((1-(2-((1-(3,4-dichlorophenylsulfonyl)-1,2,3,4-tetrahydroquinolin-2-yl)-methoxy)acetyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)-picolinamide;
(21) N-((1-(2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)-methoxy)acetyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)-picolinamide;
(22) N-((1-(2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)-methoxy)acetyl)-4-(4-(pyridin-4-yl)piperazin-1-yl)piperidin-4-yl)methyl)-acetamide;
(23) N-((1-(2-((1-(3,4-dichlorophenylsulfonyl)-1,2,3,4-tetrahydroquinolin-2-yl)methoxy)acetyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)benzamide;
(24) N-((1-(2-(2-(4-methoxy-N,2,6-trimethylphenylsulfonamido)ethoxy)acetyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)benzamide;
(25) N-((1-(2-(2-(4-methoxy-N,2,6-trimethylphenylsulfonamido)ethoxy)acetyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)picolinamide;
(26) N-((1-(3-(1-(4-chloro-2,5-dimethylphenylsulfonyl)piperidin-2-yl)propan-oyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)isonicotinamide,
(27) N-((1-(2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)-methoxy)acetyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)-acetamide;
(28) N-((1-(2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)-methoxy)acetyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)-isonicotinamide;
(29) N-((4-(4-methylpiperazin-1-yl)-1-(2-(1-(3-(trifluoromethyl)phenylsulfonyl)-piperidin-2-yl)acetyl)piperidin-4-yl)methyl)isonicotinamide;
(30) N-((1-(2-((1-(3,4-dichlorophenylsulfonyl)-1,2,3,4-tetrahydroquinolin-2-yl)methoxy)acetyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)-isonicotinamide;
(31) N-((1-(2-(2-(4-methoxy-N,2,6-trimethylphenylsulfonamido)ethoxy)acetyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)acetamide;
(32) N-((1-(2-(2-(4-methoxy-N,2,6-trimethylphenylsulfonamido)ethoxy)acetyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)nicotinamide;
(33) N-((1-(3-(1-(4-chloro-2,5-dimethylphenylsulfonyl)piperidin-2-yl)propan-oyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)nicotinamide;
(34) N-((1-(2-(1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)-meth-oxy)acetyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)-nicotinamide;
(35) N-((4-(4-methylpiperazin-1-yl)-1-(3-(naphthalene-2-sulfonamido)-3-phenylpropanoyl)piperidin-4-yl)methyl)acetamide;
(36) N-((4-(4-(pyridin-4-yl)piperazin-1-yl)-1-(2-(1-(3-(trifluoromethyl)phenyl-sulfonyl)piperidin-2-yl)acetyl)piperidin-4-yl)methyl)acetamide,
(37) N-((4-(4-methylpiperazin-1-yl)-1-(3-(naphthalene-2-sulfonamido)-3-phenylpropanoyl)piperidin-4-yl)methyl)isonicotinamide;
(38) N-((4-(4-methylpiperazin-1-yl)-1-(3-(naphthalene-2-sulfonamido)-3-phenylpropanoyl)piperidin-4-yl)methyl)nicotinamide;
(39) N-((4-(4-methylpiperazin-1-yl)-1-(2-(1-(3-(trifluoromethyl)phenylsulfonyl)-piperidin-2-yl)acetyl)piperidin-4-yl)methyl)nicotinamide;
(40) N-((1-(2-((1-(3,4-dichlorophenylsulfonyl)-1,2,3,4-tetrahydroquinolin-2-yl)-methoxy)acetyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)-nicotinamide;
(41) N-((1-(2-(2-(4-methoxy-N,2,6-trimethylphenylsulfonamido)ethoxy)acetyl)-4-(4-(pyridin-4-yl)piperazin-1-yl)piperidin-4-yl)methyl)acetamide;
(42) N-Cyclopropyl-N-(2-(2-(4-(4-cyclopropylpiperazin-1-yl)-4-((1-oxoisoindolin-2-yl)methyl)piperidin-1-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide,
(43) N-((1-(2-(2-(2-Chloro-N-cyclopropyl-6-methylphenylsulfonamido)ethoxy)-acetyl)-4-(4-cyclopropylpiperazin-1-yl)piperidin-4-yl)methyl)-isonicotinamide;
(44) N-((1-(2-(2-(N-Cyclopropyl-4-methoxy-2,6-dimethylphenylsulfonamido)-ethoxy)acetyl)-4-(4-cyclopropylpiperazin-1-yl)piperidin-4-yl)methyl)-isonicotinamide;
(45) (S)—N-((4-(4-Cyclopropylpiperazin-1-yl)-1-(2-((1-(4-methoxy-2,6-dimethyl-phenylsulfonyflindolin-2-yl)methoxy)acetyl)piperidin-4-yl)methyl)-isonicotinamide,
(46) N-((1-(2-(2-(N-Cyclopropyl-4-methoxy-2,6-dimethylphenylsulfonamido)-ethoxy)acetyl)-4-(4-(pyridin-4-yl)piperazin-1-yl)piperidin-4-yl)methyl)-acetamide;
(47) N-((1-(2-(2-(N-Cyclopropyl-2-(trifluoromethyl)phenylsulfonamido)-ethoxy)acetyl)-4-(4-cyclopropylpiperazin-1-yl)piperidin-4-yl)methyl)-isonicotinamide;
(48) N-((1-(2-(2-(4-Methoxy-N,2,6-trimethylphenylsulfonamido)ethoxy)acetyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)isonicotinamide hydrochloride;
(49) N-((1-(2-((4-(4-Methoxy-2,6-dimethylphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methoxy)acetyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)isonicotinamide
(50) N-((1-(2-((4-(2-Chloro-6-methylphenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methoxy)acetyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)isonicotinamide;
(51) N-((1-(2-(2-(4-Methoxy-N,2,3,6-tetramethylphenylsulfonamido)ethoxy)-acetyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)isonicotinamide;
(52) N-((1-(3-((1-(4-Methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)-methoxy)propanoyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)-isonicotinamide
(53) N-((1-(2-(2-(1-(4-Methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)eth-oxy)acetyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)isonicotinamide, and
(54) N-((1-(4-(N-Methyl-3-(trifluoromethyl)phenylsulfonamido)butanoyl)-4-(4-methylpiperazin-1-yl)piperidin-4-yl)methyl)isonicotinamide
or a physiologically acceptable salt thereof.

### Claim 20 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1 and at least one pharmaceutically acceptable additive or auxiliary substance, or a further active compound.

### Claim 21 (depends on 1)

A method of treating or inhibiting a disorder or disease state selected from the group consisting of pain, diabetes, asthma, allergies, chronic obstructive pulmonary disease, ulcerative colitis, Crohn's disease, multiple sclerosis, atopic dermatitis, psoriasis, rheumatoid arthritis, osteoarthritis, septic shock, reperfusion syndrome and obesity or for inhibiting angiogenesis in a subject, said method comprising administering to said subject a pharmacologically effective amount of a compound according to claim 1.

### Claim 22 (depends on 21)

A method according to claim 21, wherein said disorder or disease state is pain selected from the group consisting of acute pain, neuropathic pain, chronic pain, and inflammatory pain.