GB2397301A - Substituted 1,3,5-triazine derivatives - Google Patents

Substituted 1,3,5-triazine derivatives Download PDF

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Publication number
GB2397301A
GB2397301A GB0300805A GB0300805A GB2397301A GB 2397301 A GB2397301 A GB 2397301A GB 0300805 A GB0300805 A GB 0300805A GB 0300805 A GB0300805 A GB 0300805A GB 2397301 A GB2397301 A GB 2397301A
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GB
United Kingdom
Prior art keywords
yl
alkyl
triazin
hydrazonomethyl
compound according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
GB0300805A
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GB0300805D0 (en
Inventor
Henriette Willems
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
NOVO PHARMACEUTICALS Ltd DE
De Novo Pharmaceuticals Ltd
Original Assignee
NOVO PHARMACEUTICALS LTD DE
De Novo Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by NOVO PHARMACEUTICALS LTD DE, De Novo Pharmaceuticals Ltd filed Critical NOVO PHARMACEUTICALS LTD DE
Priority to GB0300805A priority Critical patent/GB2397301A/en
Publication of GB0300805D0 publication Critical patent/GB0300805D0/en
Publication of GB2397301A publication Critical patent/GB2397301A/en
Application status is Withdrawn legal-status Critical

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D251/00Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40Nitrogen atoms
    • C07D251/54Three nitrogen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

A compound which may have utility in the treatment of Alzheimer's disease, has the formula (I) <EMI ID=1.1 HE=60 WI=109 LX=599 LY=823 TI=CF> <PC>wherein R<1> is aryl; ```R<2> and R<3> are the same or different and are each hydrogen, alkyl, aryl, heteroaryl or -alkyl-heteroaryl, or R<2> and R<3> taken together form heterocycloalkyl; ```R 4 is aryl; and ```each R is the same or different and is hydrogen or alkyl; ```or a pharmaceutically acceptable salt thereof.

Description

239730 1

COMPOUNDS AND THEIR USE

Field of the Invention

This invention relates to compounds and their therapeutic use.

Background to the Invention

Alzheimer's disease (AD) is the most common form of dementia among older people, and affects parts of the brain that control thought, memory and language. Susceptibility to AD increases with age, but AD is not a normal part of the ageing process.

AD is associated with regions of accumulated proteins in the brain. These dense regions, termed "amyloid plaques" and "neurofibrilliary tangles", contain p-amyloid precursor protein (-APP). p-APP is degraded by pamyloid converting enzyme (BACK, also known as p-secretase) to produce pamyloid peptide Ap 40/42, which accumulates in the plaques. Research has shown that the activity of BACK is an early step in the pathogenesis pathway common to all familial and sporadic forms of AD; thus inhibitors of BACK may have therapeutic utility in the treatment of this disease.

Summarv of the Invention Compounds according to the invention are of formula (1) R2 R3

N

NON (1) NJN/1N'NR

R R

R

wherein R' is aryl; R2 and R3 are the same or different and are each hydrogen, alkyd, aryl, heteroaryl or -alkyl-heteroaryl, or R2 and R3 taken together form heterocycloalkyl; R4 is aryl; and each R is the same or different and is hydrogen or alkyl; or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a pharmaceutical composition comprising a compound of formula (1) and a pharmaceutically acceptable carrier or diluent, for use in therapy.

Another aspect of the invention is the use of a compound of formula (1) for the manufacture of a medicament for use in therapy, in particular for the treatment or prevention of AD.

Compounds of the invention are inhibitors of BACK and as a consequence may have therapeutic utility in the treatment of AD.

Description of the Invention

The present invention is based on the surprising discovery that a compound of formula (1) is an inhibitor of BACK.

For the present invention, certain compounds and combinations of substituents are preferred. In particular, see the sub-claims.

The term "alkyl" as used herein refers to a straight or branched chain alkyl moiety having from 1 to 6 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl and tert-butyl, pentyl, hexyl and the like. "C, 6" has the same meaning.

The term "aryl" as used herein refers to optionally substituted aromatic ring systems comprising six to ten ring atoms, and optionally substituted polycyclic ring systems having two or more rings at least one of which is aromatic. This term includes, for example, phenyl and naphthyl. The group may be optionally substituted in each occurrence and selected from hydroxy, alkoxy, -NHC(O)-alkyl, trihalomethyl (e.g. trifluoromethyl) and the like.

The term "heteroaryl" as used herein refers to an optionally substituted aromatic monocyclic or bicyclic ring moiety comprising 5 to 10 ring atoms at least one of which is selected from O. N and S and includes for example furanyl, thiophenyl, pyridyl, indolyl, quinolyl and the like. The substituent(s) may include alkyl and the like.

The term "heterocycloalkyl" as used herein refers to a saturated heterocyclic moiety having from 3 to 8 carbon atoms and one or more heteroatoms selected from N. O. S and includes for example azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl and the like. The substituent(s) may include halogen and the like.

The term "halogen" as used herein refers to a group selected from F. Cl, Br and 1.

Compounds of the invention may be chiral. They may be in the form of a single enantiomer or diastereomer, or a racemic mixture.

The compounds may be in the form of organic or inorganic salts, for example, the addition salts of inorganic or organic acids, e.g. hydrochloric acid, hydrobromic acid, fumaric acid, tartaric acid, citric acid and succinic acid.

Alternatively, compounds of the invention may be in the form of base addition salts, for example, salts of alkali metal hydroxides, e.g. sodium hydroxide.

A compound of the invention may be protected from, for example protected hydroxy form. The term "protected hydroxy" refers to a hydroxy group protected in a manner familiar to those skilled in the art.

As used hereinafter, the term "active compound" denotes a compound of formula (I) including pharmaceutically acceptable salts thereof.

Compounds of the invention are known or may be prepared by any suitable method known in the art.

Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallization, or by formation of a salt if appropriate or possible under the circumstances.

In therapeutic use, the active compound may be administered orally, rectally, parenterally, by inhalation (pulmonary delivery), nasally, orto the buccal cavity. Thus the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for such methods of administration. The compositions may be formulated in a manner known to those skilled in the art so as to give a desired release, for example rapid release or sustained release, of the compounds of the present invention.

Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art.

A composition of the invention is preferably administered orally.

Compositions for oral administration may be in known pharmaceutical forms, for example tablets, capsules, granules, syrups and aqueous or oily suspensions.

Tablets may be prepared from a mixture of the active compound with fillers such as lactose or calcium phosphate, disintegrating agents, for example, maize starch, lubricating agents, for example, magnesium stearate, binders, for example, microcrystalline cellulose or polyvinylpyrrolidone, and other optional ingredients known in the art to permit tableting the mixture by known methods.

The tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention.

The compositions of the invention may contain 0.1 to 99% by weight of active compound. The compositions of the invention are generally prepared in unit dosage form. Preferably, a unit dosage comprises the active ingredient in an amount of 1 to 500 mg. The excipients used in the preparation of these compositions are the excipients known in the art.

Compounds of the invention may be administered in an amount that can be determined by one of ordinary skill in the art. It will be understood that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex and diet of the patient, time of administration, route of administration, rate of excretion, drug combination and the severity of the disease.

The following compounds 1 to 9 have inhibitory activity towards BACK.

"1" 2-methoxy-4-{[4-methylamino-6-(3-trifluoromethylphenylamino)-1,3,5 triazin-2-yl]hydrazonomethyl}phenol; "2" N-(4-{[4-[(furan-2-ylmethyl)amino]-6-(4-methoxyphenylamino)-1,3,5 triazin-2-yl]hydrazonomethyl}phenyl)acetamide; "3" 6-(N'-benzylidenehydrazino)-N-methyl-N'-(3-trifluoromethylphenyl)-1,3, 5 triazine-2,4-diamine; "4" (2,3-dimethylphenyl)-[4-[N'-(4-fluorobenzylidene)hydrazino]-6-(4 methylpiperidin-1 -yl)-1,3,5-triazin-2-yl]amine; "5" N-(4-{[4-(morpholin-4-yl)-6-(naphthalen-1-ylamino)-1,3,5-triazin-2-yl] hydrazonomethyl}phenyl)acetamide; "6" 4-{[4-dimethylamino-6-(4-fluorophenylamino)-1,3,5-triazin-2-yl] hydrazonomethyl}-2-methoxyphenol; "7" 4{[4-[(furan-2-ylmethyl)amino]-6-(4-methoxyphenylamino)-1,3,5-triazin- 2 yl]hydrazonomethyl}phenol; "8" 6-[N'-(4-methoxybenzylidene)hydrazino]-N, N'-diphenyl-1, 3,5-triazine- 2,4 diamine; and "9" N-{4-[(4,6-bisphenylamino-1,3,5-triazin-2-yl)hydrazonomethyl]phenyl} acetamide.

Claims (10)

1. A compound of formula (I) R2 R3 N/N/1N'NR
R R
R
wherein R' is aryl; R2 and R3 are the same or different and are each hydrogen, alkyl, aryl, heteroaryl or -alkyl-heteroaryl, or R2 and R3 taken together form heterocycloalkyl; R4 is aryl; and each R is the same or different and is hydrogen or alkyl; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein R' is optionally substituted phenyl.
3. A compound according to claim 1 or claim 2, wherein R2 is hydrogen and R3 is alkyl, aryl or -alkyl-heteroaryl.
4. A compound according to claim 1 or claim 2, wherein R' and R2 are the same or different and are each alkyl.
5. A compound according to claim 1 or claim 2, wherein R' and R2 taken togetherform morpholinyl or piperidinyl, either of which are optionally substituted with alkyl.
6. A compound according to any preceding claim, wherein R4 is substituted with one or more substituents selected from hydroxy, alkoxy and -NHC(O)alkyl.
7. A compound according to claim 1, selected from 2-methoxy-4-{[4-methylamino-6-(3-trifluoromethylphenylamino)-1,3,5 triazin-2-yl]hydrazonomethyl}phenol; N-(4-{[4-[(furan-2-ylmethyl)amino]-6(4-methoxyphenylamino)-1,3,5 triazin-2-yl]hydrazonomethyl}phenyl) acetamide; 6-(N'-benzylidenehydrazino)-N-methyl-N'-(3-trifluoromethylphenyl)-1,3,5 triazine-2,4-diamine; (2,3-dimethylphenyl)-[4-[N'-(4-fluorobenzylidene)hydrazino]-6-(4 methylpiperidin-1 -yl)-1,3,5-triazin-2-yl]amine; N-(4-{[4-(morpholin-4-yl) -6-(naphthalen-1 -ylamino)-1,3,5-triazin-2-yl] hydrazonomethyl}phenyl) acetam ice; 4-{[4-dimethylamino-6-(4-fluorophenylamino)-1,3,5-triazin-2-yl] 1 0 hydrazonomethyl}-2-methoxyphenol; 41[4-[(furan-2-ylmethyl)amino]4-(4-methoxyphenylamino)-1,3,5-triazin-2 yl] hydrazonomethyl}phenol; 6-[N'-(4-methoxybenzylidene)hydrazino]-N, N'-diphenyl-1,3, 5-triazine-2,4 diamine; and N-{4-[(4,6-bisphenylamino-1,3,5-triazin-2-yl)hydrazonomethyl] phenyl} acetamide.
8. A compound according to any preceding claim, for therapeutic use.
9. A pharmaceutical composition comprising a compound of any of claims 1 to 7, together with a pharmaceutically acceptable carrier or diluent, for use in therapy.
10. Use of a compound of any of claims 1 to 7, for the manufacture of a medicament for use in the treatment or prevention of Alzheimer's disease.
GB0300805A 2003-01-14 2003-01-14 Substituted 1,3,5-triazine derivatives Withdrawn GB2397301A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
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Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB0300805A GB2397301A (en) 2003-01-14 2003-01-14 Substituted 1,3,5-triazine derivatives

Publications (2)

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GB2397301A true GB2397301A (en) 2004-07-21

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007051333A1 (en) * 2005-11-02 2007-05-10 Oncalis Ag Triazine beta-secretase inhibitors
EP1790345A1 (en) * 2005-11-02 2007-05-30 Esbatech AG Triazin beta-secretase inhibitors
WO2007071199A1 (en) * 2005-12-22 2007-06-28 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences 2,4-disubstituted amido-6-substituted-[1,3,5]triazine or 1,3-pyrimidine compounds, their processes for preparation, their pharmaceutical compositions and uses thereof
JP2012511549A (en) * 2008-12-12 2012-05-24 ポクセル・エスアーエスPoxel Sas Tetrahydrotriazine compounds for treating diseases associated with AMPK activity
US8389718B2 (en) 2010-07-20 2013-03-05 Vestaron Corporation Insecticidal triazines and pyrimidines
CN104974142A (en) * 2015-06-12 2015-10-14 中国人民解放军第二军医大学 Substituted triaminotriazine secreting-type aspartic protease inhibitor and preparation method thereof

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Publication number Priority date Publication date Assignee Title
GB1468225A (en) * 1973-04-05 1977-03-23 Sandoz Ltd Pyrimidinyl and s-triazinyl hydrazone derivatives
WO1999036410A1 (en) * 1998-01-13 1999-07-22 Scriptgen Pharmaceuticals, Inc. Triazine antiviral compounds
WO1999061013A2 (en) * 1998-05-22 1999-12-02 Avanir Pharmaceuticals COMPOUNDS HAVING IgE AFFECTING PROPERTIES
WO2000077246A2 (en) * 1999-06-14 2000-12-21 Novo Nordisk A/S A METHOD FOR IDENTIFYING A DRUG CANDIDATE HAVING AN INHIBITORY ACTION ON FVII-TF ACTIVITY, AND FVIIa/TF ACTIVITY INHIBITING COMPOUNDS
WO2002097862A2 (en) * 2001-05-25 2002-12-05 Optabyte, Inc. Electro luminescent devices and method of manufacturing the same
WO2003062392A2 (en) * 2002-01-18 2003-07-31 Ceretek Llc Methods of treating conditions associated with an edg receptor

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1468225A (en) * 1973-04-05 1977-03-23 Sandoz Ltd Pyrimidinyl and s-triazinyl hydrazone derivatives
WO1999036410A1 (en) * 1998-01-13 1999-07-22 Scriptgen Pharmaceuticals, Inc. Triazine antiviral compounds
WO1999061013A2 (en) * 1998-05-22 1999-12-02 Avanir Pharmaceuticals COMPOUNDS HAVING IgE AFFECTING PROPERTIES
WO2000077246A2 (en) * 1999-06-14 2000-12-21 Novo Nordisk A/S A METHOD FOR IDENTIFYING A DRUG CANDIDATE HAVING AN INHIBITORY ACTION ON FVII-TF ACTIVITY, AND FVIIa/TF ACTIVITY INHIBITING COMPOUNDS
WO2002097862A2 (en) * 2001-05-25 2002-12-05 Optabyte, Inc. Electro luminescent devices and method of manufacturing the same
WO2003062392A2 (en) * 2002-01-18 2003-07-31 Ceretek Llc Methods of treating conditions associated with an edg receptor

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* Cited by examiner, † Cited by third party
Title
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007051333A1 (en) * 2005-11-02 2007-05-10 Oncalis Ag Triazine beta-secretase inhibitors
EP1790345A1 (en) * 2005-11-02 2007-05-30 Esbatech AG Triazin beta-secretase inhibitors
WO2007071199A1 (en) * 2005-12-22 2007-06-28 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences 2,4-disubstituted amido-6-substituted-[1,3,5]triazine or 1,3-pyrimidine compounds, their processes for preparation, their pharmaceutical compositions and uses thereof
CN101245051B (en) 2005-12-22 2011-04-20 中国科学院上海药物研究所 2,4-di-substituted amido-6-substituted-[1,3,5]triazine or miazines compound, preparation method, pharmaceutical combination and use of the same
JP2012511549A (en) * 2008-12-12 2012-05-24 ポクセル・エスアーエスPoxel Sas Tetrahydrotriazine compounds for treating diseases associated with AMPK activity
US8389718B2 (en) 2010-07-20 2013-03-05 Vestaron Corporation Insecticidal triazines and pyrimidines
JP2013532659A (en) * 2010-07-20 2013-08-19 ベスタロン コーポレイション Triazine and pyrimidine insecticides
US8785630B2 (en) 2010-07-20 2014-07-22 Vestaron Corporation Insecticidal triazines and pyrimidines
CN104974142A (en) * 2015-06-12 2015-10-14 中国人民解放军第二军医大学 Substituted triaminotriazine secreting-type aspartic protease inhibitor and preparation method thereof

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Publication number Publication date
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