C5ar inhibitors for use in the treatment of chemotherapy-induced iatrogenic pain

Patent metadata

Field	Value
Publication number	US-2024398731-A1
Application number	US-202418799076-A
Country	US
Kind code	A1
Filing date	Aug 9, 2024
Priority date	Dec 12, 2017
Publication date	Dec 5, 2024
Grant date	—

Abstract

The present invention relates to C5aR inhibitor compounds, preferably C5aR noncompetitive allosteric inhibitors, useful in the treatment and/or prevention of chemotherapy-induced iatrogenic pain (CIIP).

First claim

1 . A method of preventing and/or treating chemotherapy-induced iatrogenic pain (CIIP), the method comprising administering a therapeutically effective amount of a C5aR inhibitor to a subject in need thereof.

2 . The method according to claim 1 , wherein the chemotherapy-induced iatrogenic pain is allodynia.

3 . The method according to claim 1 , wherein the C5aR inhibitor is selected from the group consisting of an (R)-arylalkylamino derivative or a pharmaceutically acceptable salt thereof, and an (R)-4-(heteroaryl)phenylethyl compound or a pharmaceutically acceptable salt thereof.

4 . The method according to claim 3 , wherein said (R)-arylalkylamino derivatives are is selected from a compound of formula (I)

or a pharmaceutically acceptable salt,
wherein
R is selected from:
2-thiazolyl or 2-oxazolyl, unsubstituted or substituted by a group selected from methyl, tert-butyl or trifluoromethyl group;
C(Ra)=N—W wherein W is linear or branched C 1 -C 4 alkyl,
CORa, SORa, SO 2 Ra, PORa, PO 2 Ra,

wherein
Ra is selected from
C 1 -C 5 -alkyl, C 3 -C 6 -cycloalkyl, C 2 -C 5 -alkenyl, unsubstituted or substituted phenyl with a group selected from halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, halo-C 1 -C 4 -alkoxy, hydroxy, C 1 -C 4 -acyloxy, phenoxy, cyano, nitro, amino;
a heteroaryl group selected from pyridine, pyrimidine, pyrrole, thiophene, furane, indole, thiazole, oxazole, such heteroaryl being unsubstituted or substituted with a group selected from halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, halo-C 1 -C 4 -alkoxy, hydroxy, C 1 -C 4 -acyloxy, phenoxy, cyano, nitro, amino;
a α or β carboxyalkyl residue consisting of straight or branched C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 2 -C 6 -alkenyl, C 1 -C 6 -phenylalkyl;
an ω-aminoalkylamino group of formula II:

wherein
X represents:
linear or branched C 1 -C 6 alkylene, C 4 -C 6 alkenylene, or C 4 -C 6 alkynylene;
a (CH 2 ) m —B—(CH 2 ) n , group,

wherein B is an oxygen, or sulfur atom, or nitrogen atom, m is zero or an integer from 2 to 3 and n is an integer from 2 to 3, or B is a CO, SO or CONH group, m is an integer from 1 to 3 and n is an integer from 2 to 3;
or X together with the nitrogen atom to which it is bound and with the R2 group forms a nitrogen containing 3-7 membered heterocyclic, monocyclic or polycyclic ring, and R3 represents hydrogen, C 1 -C 4 alkyl, C 1 -C 4 acyl, unsubstituted or substituted phenyl with a group selected from halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, hydroxy, C 1 -C 4 -acyloxy, phenoxy, cyano, nitro, amino;

R2 and R3 are independently:
hydrogen, linear or branched C 1 -C 6 alkyl, a C 3 -C 7 cycloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 -alkynyl, aryl-C 1 -C 3 -alkyl, hydroxy-C 2 -C 3 -alkyl group;
or R2 and R3 together with the N atom to which they are bound, form a 3-7 membered nitrogen heterocyclic ring of formula (III)

wherein
Y represents:
a single bond, CH2, O, S, or a N—R6 group, where R6 represents hydrogen, C 1 -C 4 alkyl, C 1 -C 4 acyl, unsubstituted or substituted phenyl with a group selected from halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, hydroxy, C 1 -C 4 -acyloxy, phenoxy, cyano, nitro, amino,

and p represents an integer from 0 to 3;
a residue of formula SO 2 R7 wherein R7 is C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 2 -C 6 -alkenyl, aryl and heteroaryl;

R1 is linear or branched C 1 -C 5 alkyl, C 3 -C 5 cycloalkyl;
Ar is a phenyl group unsubstituted or substituted by one or more groups independently selected from halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, hydroxy, C 1 -C 4 -acyloxy, phenoxy, cyano, nitro, amino, C 1 -C 4 -acylamino, halo-C 1 -C 3 -alkyl, halo-C 1 -C 3 -alkoxy, benzoyl, heteroaryl carbonyl, heteroaryl, linear or branched C 1 -C 8 -alkanesulfonate, linear or branched C 1 -C 8 -alkanesulfonamides, linear or branched C 1 -C 8 alkyl sulfonylmethyl;
or Ar is a heteroaryl ring selected from pyridine, pyrrole, thiophene, furan, indole.

5 . The method according to claim 4 , wherein
R is selected from:
2-thiazolyl or 2-oxazolyl, unsubstituted or substituted by a group selected from methyl, tert-butyl or trifluoromethyl group;
C(Ra)=N—W wherein W is linear or branched C 1 -C 4 alkyl,
CORa, SORa or SO 2 Ra,
wherein Ra is as defined above; Ar is selected from: 3′-benzoylphenyl, 3′-(4-chloro-benzoyl)-phenyl, 3′-(4-methyl-benzoyl)-phenyl, 3′-acetyl-phenyl, 3′-propionyl-phenyl, 3′-isobutanoyl-phenyl, 4′-isobutyl-phenyl, 4′-trifluoromethanesulfonyloxy-phenyl, 4′-benzenesulfonyloxy-phenyl, 4′-trifluoromethanesulfonylamino-phenyl, 4′-benzenesulfonylamino-phenyl, 4′-benzenesulfonylmethyl-phenyl, 4′-acetoxyphenyl, 4′-propionyloxy-phenyl, 4′-benzoyloxy-phenyl, 4′-acetylamino-phenyl, 4′-propionylamino-phenyl, 4′-benzoylamino-phenyl, 3′-(furan-2-carbonyl)-phenyl, 3′-(benzofuran-2-carbonyl)-phenyl, 3′-(thiophen-2-carbonyl)-phenyl, 3′-(pyridine-2-carbonyl)-phenyl, 3′-(thiazole-2-carbonyl)-phenyl, 3′-(oxazole-2-carbonyl)-phenyl, 3′-(2-furyl)-phenyl, 3′-(2-oxazolyl)-phenyl, 3′-(3-isoxazolyl)-phenyl, 3′-(2-benzoxazolyl)-phenyl, 3′-(3-benzoisoxazolyl)-phenyl, 3′-(2-thiazolyl)-phenyl, 3′-(2-pyridyl)-phenyl, 3′-(2-thiophenyl)-phenyl; or Ar is a heteroaryl ring selected from pyridine, pyrrole, thiophene, furan or indole.

6 . The method according to claim 4 , wherein
R is
2-thiazolyl, unsubstituted or substituted by a group selected from methyl or trifluoromethyl group;
CORa, SO 2 Ra, SORa;
wherein Ra is selected from:
C 1 -C 5 -alkyl, C 3 -C 5 -cycloalkyl;
phenyl, 2-pyridyl, 2-thiazolyl, 2-furyl, 2-pyrrolyl, 2-thiofenyl, 2-indolyl groups;
a carboxylalkyl group consisting of straight or branched C 1 -C 6 -alkyl, C 1 -C 6 -phenylalkyl group;
an ω-alkylamino group of formula II,

wherein
X represents:
linear or branched C 1 -C 6 alkylene, C 4 -C 6 alkenylene, C 4 -C 6 alkynylene;
or X together with the nitrogen atom to which it is bound and with the R2 group forms a nitrogen containing 3-7 membered heterocyclic monocyclic ring and R3 represents hydrogen or C 1 -C 4 alkyl;
R2 and R3 are independently hydrogen, linear or branched C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 -alkynyl;
or R2 and R3 together with the N atom to which they are bound, form a 4-6 membered nitrogen containing heterocyclic ring of formula (III)

wherein Y represents CH 2 , O, S, or a N—R6 group, where R6 represents hydrogen, C 1 -C 4 alkyl, C 1 -C 4 acyl, and p represents an integer from 0 to 2;
R1 is methyl;
Ar is selected from:
3′-benzoylphenyl, 3′-(4-chloro-benzoyl)-phenyl, 3′-(4-methyl-benzoyl)-phenyl, 3′-acetyl-phenyl, 3′-propionyl-phenyl, 3′-isobutanoyl-phenyl, 4′-isobutyl-phenyl, 4′-trifluoromethanesulfonyloxy-phenyl, 4′-benzenesulfonyloxy-phenyl, 4′-trifluoromethanesulfonylamino-phenyl, 4′-benzenesulfonylamino-phenyl, 4′-benzenesulfonylmethyl-phenyl, 4′-acetoxyphenyl, 4′-propionyloxy-phenyl, 4′-benzoyloxy-phenyl, 4′-acetylamino-phenyl, 4′-propionylamino-phenyl, 4′-benzoylamino-phenyl; 3′-(furan-2-carbonyl)-phenyl; 3′-(benzofuran-2-carbonyl)-phenyl; 3′-(thiophen-2-carbonyl)-phenyl; 3′-(pyridine-2-carbonyl)-phenyl, 3′

Assignees

• Dompe Farm Spa

Inventors

• Brandolini Laura
• Cunha Thiago Mattar
• Allegretti Marcello
• Aramini Andrea
• Bianchini Gianluca

Classifications

• A61K31/445

  Non condensed piperidines, e.g. piperocaine · CPC title

• A61K31/4406

  only substituted in position 3, e.g. zimeldine (nicotinic acid A61K31/455) · CPC title

• A61K31/426

  1,3-Thiazoles · CPC title

• A61K31/421

  1,3-Oxazoles, e.g. pemoline, trimethadione · CPC title

• A61K31/40

  having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil · CPC title