Lysophosphatidic acid derivative

Patent metadata

Field	Value
Publication number	US-11802135-B2
Application number	US-202117518212-A
Country	US
Kind code	B2
Filing date	Nov 3, 2021
Priority date	Nov 3, 2021
Publication date	Oct 31, 2023
Grant date	Oct 31, 2023

Abstract

The present invention aims to provide a compound acting as a specific agonist for LPA4 receptors, and a pharmaceutical composition containing the compound. The present invention relates to a novel lysophosphatidic acid derivative having an agonistic action on LPA4 receptors and useful for the prophylaxis and/or treatment of diseases associated with angiogenesis abnormalities involving LPA4 receptors, diseases associated with vascular disorders, or the symptoms associated therewith, and a pharmaceutical composition containing the derivative.

First claim

The invention claimed is:

1. A compound represented by the following formula (I)

wherein
X is oxygen,
Y is oxygen, —O—CH 2 —, or —CH 2 —O—,
Q is —C(═O)—,
R 1 is a group represented by the following formula (A-2)

wherein ring B is cycloalkane or benzene, R 7 in the number of n are each independently
halogen,
cyano,
optionally substituted alkyl,
optionally substituted cycloalkyl,
optionally substituted alkoxy, or
an optionally substituted aromatic hydrocarbon group, and

n is an integer of 0-5,
L 1 is R 6 —, —R 6 O—, —OR 6 —, —R 6 NH—, or —NHR 6 —,
R 6 is an optionally substituted alkylene,
R 2 is hydrogen or alkyl, and
one of R 3 and R 4 is hydrogen or optionally substituted alkyl, and the other is bonded to R 5 to form, together with a carbon atom bonded to R 3 and R 4 , a carbon bonded to R 2 , and a nitrogen atom bonded to R 5 , an optionally substituted cyclic amine,

or a pharmacologically acceptable salt thereof.

2. The compound according to claim 1 , wherein
R 6 is alkylene optionally substituted by alkyl,
R 7 in the number of n are each independently
halogen;
cyano;
alkyl optionally substituted by
halogen,
cycloalkyl, or
phenyl optionally substituted by alkyl;

cycloalkyl optionally substituted by alkyl;
an aromatic hydrocarbon group optionally substituted by
alkoxy optionally substituted by phenyl or
alkyl; or

alkoxy optionally substituted by
phenyl optionally substituted by
halogen,
alkyl,
haloalkoxy or
phenyl, or

cycloalkyl optionally substituted by alkyl,

n is 1 or 2, and
one of R 3 and R 4 is hydrogen, or alkyl optionally substituted by hydroxy or alkoxy, and the other is bonded to R 5 to form, together with a carbon atom bonded to R 3 and R 4 , a carbon bonded to R 2 , and a nitrogen atom bonded to R 5 , a cyclic amine optionally substituted by
hydroxy,
alkoxy, or
alkyl optionally substituted by hydroxy or alkoxy,

or a pharmacologically acceptable salt thereof.

3. The compound according to claim 1 , wherein
Y is oxygen or —O—CH 2 —* (wherein * denotes a binding position with a phosphorus atom),
L 1 is R 6 —, —R 6 O—, —OR 6 —, or —R 6 NH—** (wherein ** denotes a binding position with Q),
R 6 is alkylene optionally substituted by alkyl,
R 7 in the number of n are each independently
halogen;
cyano;
alkyl optionally substituted by
halogen,
cycloalkyl, or
phenyl optionally substituted by alkyl;

cycloalkyl optionally substituted by alkyl;
an aromatic hydrocarbon group optionally substituted by
alkoxy optionally substituted by phenyl, or
alkyl; or

alkoxy optionally substituted by
phenyl optionally substituted by
halogen,
alkyl,
haloalkoxy or
phenyl, or

cycloalkyl optionally substituted by alkyl,

n is 1 or 2, and
one of R 3 and R 4 is hydrogen, or alkyl optionally substituted by hydroxy or alkoxy, and the other is bonded to R 5 to form, together with a carbon atom bonded to R 3 and R 4 , a carbon bonded to R 2 , and a nitrogen atom bonded to R 5 , a cyclic amine optionally substituted by
hydroxy,
alkoxy, or
alkyl optionally substituted by hydroxy or alkoxy,

or a pharmacologically acceptable salt thereof.

4. The compound according to claim 1 , wherein
Y is oxygen,
L 1 is a single bond, —R 6 —, or —R 6 O—*** (wherein *** denotes a binding position with Q),
R 6 is alkylene,
R 7 in the number of n are each independently
halogen;
alkyl optionally substituted by
halogen,
cycloalkyl, or
phenyl optionally substituted by alkyl;

cycloalkyl;
phenyl optionally substituted by alkyl; or
alkoxy optionally substituted by
phenyl optionally substituted by
halogen,
alkyl,
haloalkoxy or
phenyl, or

cycloalkyl,

n is 1 or 2, and
one of R 3 and R 4 is hydrogen, and the other is bonded to R 5 to form, together with a carbon atom bonded to R 3 and R 4 , a carbon bonded to R 2 , and a nitrogen atom bonded to R 5 , azetidine, pyrrolidine or piperidine each optionally substituted by
hydroxy,
alkoxy, or
alkyl optionally substituted by hydroxy or alkoxy,

or a pharmacologically acceptable salt thereof.

5. The compound of claim 1 , wherein
Y is oxygen,
L 1 is a single bond, —R 6 —, or —R 6 O—*** (wherein *** denotes a binding position with Q),
R 6 is alkylene,
R 2 is hydrogen, and
one of R 3 and R 4 is hydrogen, and the other is bonded to R 5 to form, together with a carbon atom bonded to R 3 and R 4 , a carbon bonded to R 2 , and a nitrogen atom bonded to R 5 , azetidine optionally substituted by
hydroxy,
alkoxy, or
alkyl optionally substituted by hydroxy or alkoxy,

or a pharmacologically acceptable salt thereof.

6. The compound of claim 1 , wherein ring B is benzene, or a pharmacologically acceptable salt thereof.

7. The compound according to claim 1 , wherein the compound of the formula (I) is any of the following a to i, or a pharmacologically acceptable salt thereof:
a. 1-[9-(4-ethylphenyl)nonanoyl]azetidin-3-yl dihydrogen phosphate,
b. 1-{4-[4-(octyloxy)phenyl]butanoyl}azetidin-3-yl dihydrogen phosphate,
c. 1-[8-(3-octylphenyl)octanoyl]azetidin-3-yl dihydrogen phosphate,
d. 1-[9-(4-butylphenyl)nonanoyl]azetidin-3-yl dihydrogen phosphate,
e. 1[9-(biphenyl-4-yl)nonanoyl]azetidin-3-yl dihydrogen phosphate,
f. 1-[9-(4-tert-butylphenyl)nonanoyl]azetidin-3-yl dihydrogen phosphate,
g. 1-[9-(4-cyclopropylphenyl)nonanoyl]azetidin-3-yl dihydrogen phosphate,
h. 1-[9-(4-cyclohexylphenyl)nonanoyl]azetidin-3-yl dihydrogen phosphate, and
i. 1-[9-(4-hexylphenyl)nonanoyl]azetidin-3-yl dihydrogen phosphate.

8. A pharmaceutical composition comprising the compound according to claim 1 or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable carrier.

9. A pharmaceutical composition according to claim 8 for use in the treatment of a disease associated with angiogenesis abnormality, or a disease associated with a vascular disorder.

10. The pharmaceutical composition according to claim 8 for use in combination with an anticancer drug.

11. The pharmaceutical composition according to claim 10 , wherein the anticancer drug is a drug for treating a disease associated with angiogenesis abnormality, or a disease associated with a vascular disorder.

12. The pharmaceutical composition according to claim 10 , wherein the anticancer drug is at least one kind of drug selected from the group consisting of a chemotherapeutic agent, an immunotherapeutic agent, and a hormonal therapeutic agent.

13. The pharmaceutical composition according to claim 10 , wherein the compound or a pharmacologically acceptable salt thereof, and the anticancer drug are separately administered.

14. The pharmaceutical composition according to claim 10 , wherein the compound or a pharmacologically acceptable salt thereof, and the anticancer drug are simultaneously or sequentially administered.

15. The pharmaceutical composition according to claim 9 , wherein the disease associated with angiogenesis abnormality, or the disease associated with a vascular disorder is solid cancer, pressure ulcer, diabetic necrosis, diabetic nephropathy, diabetic retinopathy, acute nephropathy, cerebral infarction, age-related macular degeneration, rheumatoid arthritis, scleroderma, psoriasis, systemic lupus erythematosus, lung fibrosis, arteriosclerosis obliterans, arteriosclerosis, angina pectoris, myocardial i

Assignees

• Mitsubishi Tanabe Pharma Corp
• Univ Osaka

Inventors

• Hamada Maiko
• Arai Yuki
• Yamakoshi Shuhei
• Wada Hiroko
• Otsuki Kazufumi
• Shitama Hiroaki
• Takakura Nobuyuki

Classifications

• C07F9/568 Primary

  Four-membered rings · CPC title

• A61K45/06 Primary

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07F9/58

  Pyridine rings · CPC title

• C07F9/6512

  having the nitrogen atoms in positions 1 and 3 · CPC title

• C07F9/091

  with hydroxyalkyl compounds with further substituents on alkyl · CPC title