CYCLOPROPANAMINE COMPOUND AND USE THEREOF

• US 20170029417A1
• Filed: 04/09/2015
• Published: 02/02/2017
• Est. Priority Date: 04/11/2014
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Takeda Pharmaceutical Company Limited
• Inventors: MATSUMOTO, Shigemitsu, HATTORI, Yasushi, TOYOFUKU, Masashi, MORIMOTO, Shinji, DAINI, Masaki, KOJIMA, Takuto, KAKU, Tomohiro, ITO, Mitsuhiro
• Granted Patent: US 10,053,456 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 213/82 in position 3
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/14 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 277/56 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 285/08 1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
• CPC Class Codes: C07D 285/135 Nitrogen atoms
• CPC Class Codes: C07D 307/79 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 307/81 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 333/38 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 333/40 Thiophene-2-carboxylic acid
• CPC Class Codes: C07D 407/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings

Abstract

The present invention provides a compound having a lysine-specific demethylase-1 inhibitory action, and useful as a medicament such as a prophylactic or therapeutic agent for schizophrenia, developmental disorders, particularly diseases having intellectual disability (e.g., autistic spectrum disorders, Rett syndrome, Down'"'"'s syndrome, Kabuki syndrome, fragile X syndrome, Kleefstra syndrome, neurofibromatosis type 1, Noonan syndrome, tuberous sclerosis), neurodegenerative diseases (e.g., Alzheimer'"'"'s disease, Parkinson'"'"'s disease, spinocerebellar degeneration (e.g., dentatorubural pallidoluysian atrophy) and Huntington'"'"'s disease), epilepsy (e.g., Dravet syndrome) or drug dependence, and the like. A compound represented by the formula wherein each symbol is as defined in the present specification, or a salt thereof.

Claims

1. A compound represented by the formula

2. The compound according to claim 1, wherein A is

(1) an optionally substituted heterocyclic group, or

(2) an optionally substituted C_3-10 cycloalkyl group, or a salt thereof.

3. The compound according to claim 1, wherein B is a ring selected from

(1) a 5- or 6-membered aromatic heterocycle, and

(2) a benzene ring fused with an optionally substituted 5- or 6-membered ring,

wherein the ring represented by B is optionally substituted, and binds, via two adjacent carbon atoms with one atom in between, to a group represented by the formula (II), and a group represented by the formula (III),

or a salt thereof.

4. The compound according to claim 1, wherein, in the formula

5. The compound according to claim 1, wherein R¹, R² and R⁴ are each independently a hydrogen atom or an optionally substituted C_1-6 alkyl group,

or a salt thereof.

6. The compound according to claim 1, wherein R³ is

(1) a hydrogen atom,

(2) an optionally substituted C_1-6 alkyl group,

(3) an optionally substituted C_3-10 cycloalkyl group, or

(4) an optionally substituted heterocyclic group,

or a salt thereof.

7. The compound according to claim 1, wherein, in the formula

8. The compound according to claim 1, wherein A is

(1) a piperidinyl group, an isoxazolyl group, a pyrazolyl group, a thiadiazolyl group, a thiazolyl group, a tetrahydropyranyl group, an Oxetanyl group, an oxadiazolyl group, a thienyl group, a pyridyl group or an oxazolyl group, each of which is optionally substituted by C_1-6 alkyl group(s) optionally substituted by halogen atom(s), or

(2) a C3-10 cycloalkyl group optionally substituted by halogen atom(s);

B is a ring selected from

thiophene, thiazole, pyrazole, pyridine, naphthalene and 2,3-dihydrobenzofuran, wherein the ring is optionally substituted m by C_1-6 alkyl group(s);

R¹ is a hydrogen atom;

R² is a hydrogen atom;

R³ is

(1) a hydrogen atom,

(2) a C_1-6 alkyl group optionally substituted by substituent(s) selected from

(a) a C_3-10 cycloalkyl group,

(b) a C_6-14 aryl group optionally substituted by carboxy group(s),

(c) a tetrahydropyranyl group or a piperidinyl group each optionally substituted by C_1-6 alkyl group(s) optionally substituted by substituent(s) selected from a carboxy group, and a C_6-14 aryl group optionally substituted by carboxy group(s), and

(d) an oxadiazolyl group optionally substituted by an amino group,

(3) a C_3-10 cycloalkyl group optionally substituted by substituent(s) selected from an amino group and a halogen atom or

(4) a tetrahydropyranyl group or a piperidinyl group each optionally substituted by substituent(s) selected from

(a) a C_1-6 alkyl group optionally substituted by halogen atom(s),

(b) a C_3-10 cycloalkyl group,

(c) a C_1-6 alkyl-carbonyl group, and

(d) a C_3-10 cycloalkyl-carbonyl group; and

R⁴ is a hydrogen atom,

or a salt thereof.

9. The compound according to claim 1, wherein A is

(1) a pyrazolyl group, a thiadiazolyl group or a tetrahydropyranyl group, each optionally substituted by C_1-6 alkyl group(s), or

(2) a cyclohexyl group optionally substituted by halogen atom(s);

B is

a thiophene ring, which ring is optionally substituted by C_1-6 alkyl group(s);

R¹ is a hydrogen atom;

R² is a hydrogen atom;

R³ is a cyclopropylmethyl group, a tetrahydropyranylmethyl group, a cyclobutylmethyl group, a cyclobutyl group or a tetrahydropyranyl group; and

R⁴ is a hydrogen atom,

or a salt thereof.

10. The compound according to claim 1, wherein A is a pyrazolyl group, a thiadiazolyl group or a tetrahydropyranyl group, each optionally substituted by C_1-6 alkyl group(s),

B is

a thiophene ring, which ring is optionally substituted by C_2-6 alkyl group(s);

R¹ is a hydrogen atom;

R² is a hydrogen atom;

R³ is a cyclopropylmethyl group or a cyclobutyl group; and

R⁴ is a hydrogen atom,

or a salt thereof.

14. A medicament comprising the compound according to claim 1 or a salt thereof.

15. The medicament according to claim 14, which is an LSD1 inhibitor.

16. The medicament according to claim 14, which is a prophylactic or therapeutic agent for schizophrenia, developmental disorders, autistic spectrum disorders, Rett syndrome, Down'"'"'s syndrome, Kabuki syndrome, fragile X syndrome, Kleefstra syndrome, neurofibromatosis type 1, Noonan syndrome, tuberous sclerosis, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, spinocerebellar degeneration, Huntington'"'"'s disease, epilepsy or drug dependence.

17. The compound according to claim 1 or a salt thereof for use in the prophylaxis or treatment of schizophrenia, developmental disorders, autistic spectrum disorders, Rett syndrome, Down'"'"'s syndrome, Kabuki syndrome, fragile X syndrome, Kleefstra syndrome, neurofibromatosis type 1, Noonan syndrome, tuberous sclerosis, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, spinocerebellar degeneration, Huntington'"'"'s disease, epilepsy or drug dependence.

18. A method of inhibiting LSD1 in a mammal, comprising administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal.

19. A method for the prophylaxis or treatment of schizophrenia, developmental disorders, autistic spectrum disorders, Rett syndrome, Down'"'"'s syndrome, Kabuki syndrome, fragile X syndrome, Kleefstra syndrome, neurofibromatosis type 1, Noonan syndrome, tuberous sclerosis, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, spinocerebellar degeneration, Huntington'"'"'s disease, epilepsy or drug dependence in a mammal, comprising administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal.

20. Use of the compound according to claim 1 or a salt thereof in the production of a prophylactic or therapeutic agent for schizophrenia, developmental disorders, autistic spectrum disorders, Rett syndrome, Down'"'"'s syndrome, Kabuki syndrome, fragile X syndrome, Kleefstra syndrome, neurofibromatosis type 1, Noonan syndrome, tuberous sclerosis, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, spinocerebellar degeneration, Huntington'"'"'s disease, epilepsy or drug dependence.

11. 5-((1R,2R)-2-((Cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamide or a salt thereof.

12. 4-((1S,2R)-2-(Cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamide or a salt thereof.

13. 4-((1S,2R)-2-(Cyclobutylamino)cyclopropyl)-5-methyl-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamide or a salt thereof.