Compounds with biguanidyl radical and uses thereof

Patent metadata

Field	Value
Publication number	US-12415781-B2
Application number	US-201915734569-A
Country	US
Kind code	B2
Filing date	Jun 4, 2019
Priority date	Jun 5, 2018
Publication date	Sep 16, 2025
Grant date	Sep 16, 2025

Abstract

The present invention relates to new compounds of formula (I), and their uses.

First claim

The invention claimed is:

1. A method for targeting mitochondrial copper, comprising the administration, to a subject in need thereof, of a compound of formula (I), a conjugate thereof or a pharmaceutical composition comprising said compound or conjugate, said conjugate comprising a drug or a toxin conjugated to an alkyne group in said compound via an azide (N 3 ) group, wherein compound of formula (I) is:

wherein
R 1 is selected from the group consisting of a C 1 -C 6 alkyl, —(CH 2 ) a —C≡CH, —(CH2) b —P + Ph 3 , a C 3 -C 10 cycloalkyl, a C 3 -C 10 cycloheteroalkyl, a C 6 -C 12 aryl, and a C 5 -C 12 heteroaryl, with “a” being an integer selected from 1 to 6 and “b” being an integer selected from 5 to 11 said alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl being optionally substituted by a R group or a R′ group; and
R 2 is selected from the group consisting of
—(CH 2 ) d —C≡CH, with “d” being an integer selected from 1 to 6; and
—(CH 2 ) e —CH≡CH 2 with “e” being an integer selected from 2 to 6;

or
R 1 is selected from the group consisting of H, a C 1 -C 6 alkyl, —(CH 2 ) a —C≡CH, —(CH 2 ) b —P + Ph 3 , a C 3 -C 10 cycloalkyl, a C 3 -C 10 cycloheteroalkyl, a C 6 -C 12 aryl, and a C 5 -C 12 heteroaryl, with “a” being an integer selected from 1 to 6 and “b” being an integer selected from 5 to 11, said alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl being optionally substituted by a R group or a R′ group;
R 2 is selected from the group consisting of
—(CH 2 ) f —CR 4 ═CH—CH═CR 5 —(CH 2 ) g —R 3 with R 4 and R 5 being H, a R group or forming together a six-member ring, optionally substituted by one or two R′ groups or fused with a cycloalkyl, an aryl, a cycloheteroalkyl or a heteroaryl having 3 to 6 members, “f” and “g” being an integer independently selected from 1 to 3;
—(CH 2 ) f —C≡C—C≡C—(CH 2 ) g —R 3 , with “f” and “g” being an integer independently selected from 1 to 3;
—(CH 2 ) i —R 3 , with “i” being an integer selected from 7 to 9;
—(CH 2 ) j —CH[(CH 2 ) k —P + Ph 3 ]—(CH 2 ) l —R 3 with “j” and “l” being integer independently selected from 1 to 6, and “k” being an integer selected from 1 to 6;
—(CH 2 ) m -cyclobutanyl-(CH 2 ) n —R 3 with “m” and “n” being an integer independently selected from 1 to 3; and
—(CH 2 ) p —CHR 6 —CH═CH—CHR 7 —(CH 2 ) q —R 3 with R 6 and R 7 being H, a R group or forming together a 4-6 member ring, optionally substituted by one or two R′ groups or fused with a cycloalkyl, an aryl, a cycloheteroalkyl or a heteroaryl having 3 to 6 members, “p” and “q” being an integer independently selected from 1 to 3; and

R 3 is

with R 8 selected from the group consisting of H, a C 1 -C 6 alkyl, —(CH 2 ) a —C≡CH, —(CH2) b —P + Ph 3 , a C 3 -C 10 cycloalkyl, a C 3 -C 10 cycloheteroalkyl, a C 6 -C 12 aryl, and a C 5 -C 12 heteroaryl, with “a” being an integer selected from 1 to 6 and “b” being an integer selected from 5 to 11 said alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl being optionally substituted by a R group or a R′ group; and

wherein
R is selected from the group consisting of a C 1 -C 6 alkyl, a C 1 -C 6 alkyloxy, a C 1 -C 6 halogenoalkyl, a C 3 -C 10 cycloalkyl, a C 3 -C 10 cycloheteroalkyl, a C 6 -C 12 aryl, and a C 5 -C 12 heteroaryl, the group being optionally substituted by a group R′,
R′ is selected from the group consisting of a C 1 -C 6 alkyl, a C 1 -C 6 alkyloxy, a C 1 -C 6 thioalkyl, a halogen, a C 1 -C 6 halogenoalkyl, a hydroxyl (—OH), a cyano (—CN), a nitro, an amino (—NH 2 ), a carboxyl (—COOH), a phosphate (PO 4 − ), an amide (—CONH 2 ), —COOR″, —NHR″, —NR″R′″, —COR″, —CONHR″, —NHCOR″, —NHSO 2 R″, —SOR″, —SO 2 R″, —SONR″R′″, —SO2NR″R′″, a C 3 -C 10 cycloalkyl, a C 3 -C 10 cycloheteroalkyl, a C 6 -C 12 aryl, and a C 5 -C 12 heteroaryl, said cycloalkyl, cycloheteroalkyl, aryl or heteroaryl being optionally substituted by a halogen, a hydroxyl, a cyano, a nitro, an amino, or a C 1 -C 3 alkoxy, with R″ and R′″ being H or a C 1 -C 6 alkyl;

or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein the subject has a disease or a disorder selected from the group consisting of: cancer, diabetes, diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, preeclampsia, liver and kidney diseases, fatty liver, cardiovascular diseases, coronary artery disease, osteoporosis, metabolic syndrome, multiple sclerosis, polycystic ovary disease, muscle pain, myocyte damage, rhabdomyolysis, erectile dysfunction, cognitive dysfunction, modulation of gut microbiota, neurodegenerative disorders and diseases, Alzheimer's disease, and Parkinson's disease.

3. The method of claim 2 , wherein the subject has a cancer.

4. The method of claim 3 , wherein the subject has a cancer with mesenchymal cells.

5. The method of claim 1 , wherein the subject has a cancer selected from the group consisting of rectal cancer, colorectal cancer, stomach cancer, head and neck cancer, thyroid cancer, cervical cancer, uterine cancer, breast cancer, triple negative breast cancer, ovarian cancer, brain cancer, glioblastoma, neuroblastoma, lung cancer, small-cell lung cancer, non-small-cell lung cancer, skin cancer, bladder cancer, blood cancer, renal cancer, liver cancer, prostate cancer, multiple myeloma, and endometrial cancer.

6. The method of claim 1 , for treating a disease or a disorder selected from the group consisting of: cancer, diabetes, diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, preeclampsia, liver and kidney diseases, fatty liver, cardiovascular diseases, coronary artery disease, osteoporosis, metabolic syndrome, multiple sclerosis, polycystic ovary disease, muscle pain, myocyte damage, rhabdomyolysis, erectile dysfunction, cognitive dysfunction, modulation of gut microbiota, neurodegenerative disorders and diseases, Alzheimer's disease, and Parkinson's disease.

7. The method of claim 1 , for treating cancer.

8. The method of claim 7 , for treating a cancer with mesenchymal cells.

9. The method of claim 8 , for treating a cancer selected from the group consisting of rectal cancer, colorectal cancer, stomach cancer, head and neck cancer, thyroid cancer, cervical cancer, uterine cancer, breast cancer, triple negative breast cancer, ovarian cancer, brain cancer, glioblastoma, neuroblastoma, lung cancer, small-cell lung cancer, non-small-cell lung cancer, skin cancer, bladder cancer, blood cancer, renal cancer, liver cancer, prostate cancer, multiple myeloma, and endometrial cancer.

10. The method of claim 1 , further comprising treatment comprising radiotherapy chemotherapy, hormonotherapy or immunotherapy.

11. The method of claim 1 , wherein R 3 is present in the compound.

12. The method of claim 1 , wherein R 2 is selected from the group consisting of
—(CH 2 ) d —C≡CH, with “d” being an integer selected from 2 to 4 ;
—(CH 2 ) e —CH—CH 2 with “e” being an integer selected from 2 to 4;
—(CH 2 ) f —CR 4 ═CH—CH═CR 5 —(CH 2 ) g —R 3 with R 4 and R 5 being H, a R group or forming together a six-member ring, optionally substituted by one or two R′ groups or fused with a cycloalkyl, an aryl, a cycloheteroalkyl or a heteroaryl having 3 to 6 members, “f” and “g” being an integer independently selected from 1 to 3, and “f”+“g” being from 2 to 4;
—(CH 2 ) f —C≡C—C≡C—(CH 2 ) g —R 3 , with “f” and “g” being an integer independently selected from 1 to 3, and “f”+“g” being from 2 to 4;
—(CH 2 ) i —R 3 ,

Assignees

• Inst Curie
• Centre Nat Rech Scient
• Inserm Institut De La Sante Et De La Rech Medicale
• Inst Nat Sante Rech Med

Inventors

• Cañeque Tatiana
• Muller Sebastian
• Rodriguez Raphaël

Classifications

• A61K45/06

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

• A61P35/00

  Antineoplastic agents · CPC title

• C07F9/5442

  Aromatic phosphonium compounds (P-C aromatic linkage) · CPC title

• C07C279/265 Primary

  containing two or more biguanide groups · CPC title

• C07D405/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title