GB2307858A - Compositions containing piperazine derivatives for the treatment of cancer - Google Patents
Compositions containing piperazine derivatives for the treatment of cancer Download PDFInfo
- Publication number
- GB2307858A GB2307858A GB9625316A GB9625316A GB2307858A GB 2307858 A GB2307858 A GB 2307858A GB 9625316 A GB9625316 A GB 9625316A GB 9625316 A GB9625316 A GB 9625316A GB 2307858 A GB2307858 A GB 2307858A
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- Prior art keywords
- alkyl
- aryl
- cycloalkyl
- heteroaryl
- hydrogen
- Prior art date
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- Granted
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 11
- 201000011510 cancer Diseases 0.000 title claims abstract description 11
- 150000004885 piperazines Chemical class 0.000 title claims abstract description 6
- 239000000203 mixture Substances 0.000 title description 16
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 title description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 50
- 125000003118 aryl group Chemical group 0.000 claims abstract description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 15
- 239000001257 hydrogen Substances 0.000 claims abstract description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 15
- 239000002253 acid Substances 0.000 claims abstract description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- -1 alkyl radical Chemical class 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 20
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 19
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 150000003254 radicals Chemical class 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 150000005840 aryl radicals Chemical group 0.000 claims description 3
- 125000002950 monocyclic group Chemical group 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- 239000007788 liquid Substances 0.000 description 11
- 239000004480 active ingredient Substances 0.000 description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
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- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
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- 229920002472 Starch Polymers 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- XTFIVUDBNACUBN-UHFFFAOYSA-N 1,3,5-trinitro-1,3,5-triazinane Chemical compound [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)C1 XTFIVUDBNACUBN-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- 102100022738 5-hydroxytryptamine receptor 1A Human genes 0.000 description 1
- 101710138638 5-hydroxytryptamine receptor 1A Proteins 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 235000003911 Arachis Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- UMTDAKAAYOXIKU-UHFFFAOYSA-N N-tert-butyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-phenylpropanamide Chemical compound COC1=CC=CC=C1N1CCN(CC(C(=O)NC(C)(C)C)C=2C=CC=CC=2)CC1 UMTDAKAAYOXIKU-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical group [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000005036 alkoxyphenyl group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
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- 239000003086 colorant Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
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- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
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- 230000004634 feeding behavior Effects 0.000 description 1
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- 125000005843 halogen group Chemical group 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 150000002913 oxalic acids Chemical class 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000036299 sexual function Effects 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
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- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000006169 tetracyclic group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The use of a piperazine derivative of general formula I: or a pharmaceutically acceptable acid addition salt thereof, in the treatment of cancer, wherein: R is hydrogen or lower alkyl, R 1 is an aryl or heteroaryl (especially nitrogen containing heteroaryl) radical, and X is a group of formula -(CH 2 )n CR 2 R 3 .CONR 4 R 5 ```(IIa) or -A-NR 6 COR 7 ```(IIb) R 2 -R 7 are as defined herein.
Description
MEDICAL TREATMENT
This invention relates to the use of certain piperazine derivatives in the treatment of cancer.
The piperazine derivatives are those of general formula
and the pharmaceutically acceptable acid addition salts thereof
In formula (I)
R is hydrogen or lower alkyl, R1 is an aryl or heteroaryl (preferably nitrogen containing heteroaryl) radical, and X is a group of formula
-(CH2)n CR2R3.CONR4R5 (IIa) or
-A-NR6COR7 (IIb) where n is one of the integers 1 or 2;
R2 is hydrogen or lower alkyl;;
R3 is an aryl radical or an aryl(lower)alkyl radical,
R4 is hydrogen or lower alkyl
R5 is hydrogen, an alkyl group of 1 to 8 carbon atoms, cycloalkyl of 3 to 12 carbon atoms or cycloalkyl(lower)alkyl, or R4 and R5 together with the nitrogen atom to which they are attached represent an azetidino, pyrrolidino, piperidino, hexahydroazepino, morpholino or piperazino ring which may be optionally substituted by lower alkyl, aryl or aryl(lower)alkyl.
A is an alkylene chain of 2 to 4 carbon atoms optionally substituted by one or more lower alkyl groups,
R6 is a mono or bicyclic heteroaryl radical and R7 is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkyl(lower)alkyl, aryl, aryl(lower)alkyl, heteroaryl, heteroaryl(lower)alkyl, a group of formula -NR8R9 [where
R8 is hydrogen, lower alkyl, aryl or aryl(lower)alkyl and R9 is hydrogen, lower alkyl, -CO(lower)alkyl, aryl, COaryl, aryl(lower)alkyl, cycloalkyl or cycloalkyl(lower)alkyl or
R8 and R9 together with the nitrogen atom to which they are both attached represent a saturated heterocyclic ring which may contain a further hetero atom] or a group of formula OR10[where R10 is lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, aryl, aryl(lower)alkyl, heteroaryl or heteroaryl(lower)alkyl].
Preferred compounds of formula I are those of formula II
or the pharmaceutically acceptable acid addition salts thereof (where n, R, R1, R2, R3,
R4 and R5 are as defined above).
The term "lower" as used herein means that the radical referred to contains 1 to 6 carbon atoms. Preferably such radicals contain 1 to 4 carbon atoms. Examples of "lower alkyl" radicals are methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and isopentyl.
Examples of cycloalkyl groups are cyclopentyl, cyclohexyl and cycloheptyl. A preferred example is cyclohexyl. Cycloalkyl groups include bicyclic, tricyclic and tetracyclic groups, eg adamantyl. Preferably the cycloalkyl group contains 3 to 12 carbon atoms.
When used herein "aryl" means an aromatic radical having 6 to 12 carbon atoms (eg phenyl or naphthyl) which optionally may be substituted by one or more substituents.
Preferred substituents are lower alkyl, lower alkoxy (eg methoxy, ethoxy, propoxy, butoxy), halogen, halo(lower)alkyl (eg trifluoromethyl), nitro, nitrile, amido, (lower)alkoxycarbonyl, amino, (lower)alkylamino or di(lower)alkylamino substituents. Two substituents on the aromatic ring may be connected together to form another ring system.
When R1 is an aryl radical it is preferably a phenyl radical containing a substituent in the ortho position. A preferred example of R1 is o-(lower)alkoxyphenyl eg o- methoxyphenyl. R1 can also be, for example a l-naphthyl radical optionally substituted in the 2 or 7 positions by, for example, (lower)alkoxy.
Preferred examples of aryl(lower)alkyl are benzyl and phenethyl in which the phenyl rings may be substituted by substituents as given above.
When used herein "nitrogen containing heteoraryl radical" means an aromatic ring containing one or more nitrogen atoms as heteroatoms (eg pyridinyl, pyrimidinyl or pyrazinyl) which may optionally be substituted by one or more lower alkyl, lower alkoxy, halogen, trifluoromethyl, amino, (lower)alkylamino or di (lower) alkylamino substituents. Preferably the heteroaryl radical is monocyclic.
When R6 is a bicyclic heteroraryl radical both rings of the radical may contain hetero ring atoms or only one ring may contain a hetero atom or atoms. In the latter instance the radical R6 is connected to the rest of the molecule of formula (I) via the ring containing the hetero atom(s).
Examples of the heteroaryl radical R6 include monocyclic radicals containing one hetero atom, eg optionally substituted pyridyl (particularly 2-pyridyl), monocyclic radicals containing two hetero atoms, eg thiazolyl (particularly 2-thiazolyl) and bicyclic radicals containing one or two hetero atoms eg quinolinyl or isoquinolinyl (particularly 2quinolinyl).
The piperazine derivatives of formula (I) and their method of preparation are disclosed, for example, in
GB 2230780A GB 2230781A GB 2248836A and GB 2255337A.
The compounds disclosed in GB 2230780A are described as antidepressant and/or anxiolytic agents. The compounds disclosed in GB 2230781 A, GB 2248836A and GB 2255337A are disclosed as 5-HT1A antagonists useful as antidepressants hypotensives and as agents for regulating the sleep/wake cycle, feeding behaviours and/or sexual function.
The preferred compounds of formula (I) are:
N-tert-butyl-3-[4-(2-methoxyphenyl)piperazin- 1-yl]-2phenylpropanamide and its (+)-enantiomer 2,3,4,5,6,7-hexahydro- 1 -[4-[ 1 -[4-(2-methoxyphenyl)- piperazinyl]]-2-phenyl]butanoyl- lH-azepine (-)-(R) -2,3,4,5,6,7 -hexahydro- 1 -[4-[4-(2methoxyphenyl)piperazin- 1 -yl] -2-phenyl]butanoyl- 1 H- azepine N- [2- [4-(2-methoxyphenyl)- l-piperazinyl]ethyl]
N-(2-pyridinyl)cyclohexanecarboxamide and their pharmaceutically acceptable acid addition salts.
The present invention provides in one aspect, a method of treating cancer which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable acid addition salt thereof. In a second aspect the invention provides the use of a compound of formula (I) as defined above or a pharmaceutically acceptable acid addition salt thereof for the manufacture of a medicament for the treatment of cancer. Suitably, the mammal is a human.
In this specification the terms "treatment" and "treating" relate to the administration of the compounds to prevent the disorder as well as to treat the disorder or to alleviate the symptoms of the disorder.
The term 'cancer' as used herein includes carcinoma, especially small cell lung carcinoma and prostatic carcinoma.
The compounds may be used in treating cancer in their free base form or as acid addition salts.
Examples of acid addition salts are those formed from inorganic and organic acids, such as sulphuric, hydrochloric, hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, formic, methanesulphonic, p-toluenesulphonic, oxalic and succinic acids.
The compounds of formula I contain one or more asymmetric carbon atoms, so that the compounds can exist in different steroisomeric forms. The compounds can, for example, exist as racemates or optically active forms.
The compounds may be used for treating cancer in the form of pharmaceutical compositions which comprise a compound of formula I or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutically acceptable carrier. Any suitable carrier known in the art can be used to prepare the pharmaceutical composition.
In such a composition, the carrier is generally a solid or liquid or a mixture of a solid or liquid.
Solid form compositions include powders, granules, tablets, capsules (eg hard and soft gelatine capsules), suppositories and pessaries. A solid carrier can be, for example, one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, fillers, glidants, compression aides, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99%, eg from 0.03 to 99%, preferably 1 to 80% of the active ingredient.Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
The term "composition" is intended to include the formulation of an active ingredient with encapsulating material as carrier to give a capsule in which the active ingredient (with or without other carriers) is surrounded by the carrier, which is thus in association with it. Similarly cachets are included.
Liquid form compositions include, for example, solutions, suspensions, emulsions, syrups, elixirs and pressurised compositions. The active ingredient, for example, can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilisers, emulsifiers, buffers, preservatives, sweeteners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators, stabilisers or osmo-regulators.Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, eg cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols, eg glycerol and glycols) and their derivatives, and oils (eg fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. When the compound is orally active it can be administered orally either in liquid or solid composition form.
Preferably the pharmaceutical composition is in unit dosage form, eg as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged composition, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquid. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
The quantity of the active ingredient in unit dose of composition may be varied or adjusted from 0.5 mg or less to 750 mg or more, according to the particular need and the activity of the active ingredient.
The following Examples illustrate the invention:
Example 1
Preparation of Tablets
Amount per tablet mg (-)-(R)-2,3,4,5,6,7 Hexahydro- 1 -[4-[4-(2- methoxyphenyl)piperazin- 1 - yl]-2-phenyl]butanoyl-1H- azepine 1 5 10
Microcrystalline cellulose 49.25 47.25 44.75
Modified food corn starch 49.25 47.25 44.75
Magnesium stearate 0.5 0.5 0.5
Tablets are prepared from bulk amounts of ingredients in the proportions given above.
All of the active compound, cellulose and a portion of the corn starch are mixed and granulated to 10% corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing 1, 5 and 10 mg of the active ingredient per tablet.
Example 2
Preparation of powder filled capsules
Amount mg
N-tert.butyl-3-[4-(2 methoxyphenyl)piperazin- 1 - yl]-2-phenylpropanamide 10 15
Avicel 45
Lactose 153
Starch (1500 NF) 117
Sodium starch glycollate - 6
Magnesium stearate 2 2
The formulations are prepared by admixing the ingredients in the proportions given above and filling two-part hard gelatin capsules with the required amount of the resulting mixture to give capsules containing 10 or 15 mg of the active compound.
Claims (4)
1. The use of a piperazine derivative of general formula I:
or a pharmaceutically acceptable acid addition salt thereof, in the treatment of cancer, wherein:
R is hydrogen or lower alkyl,
R1 is an aryl or heteroaryl (especially nitrogen containing heteroaryl) radical, and X is a group of formula
-(CH2)n CR2R3.CONR4R5 (IIa) or
-A-NR6COR7 (ITh) where n is one of the integers 1 or 2;
R2 is hydrogen or lower alkyl;;
R3 is an aryl radical or an aryl(lower)alkyl radical,
R4 is hydrogen or lower alkyl
R5 is hydrogen, an alkyl group of 1 to 8 carbon atoms, cycloalkyl of 3 to 12 carbon atoms or cycloalkyl(lower)alkyl, or R4 and R5 together with the nitrogen atom to which they are attached represent an azetidino, pyrrolidino, piperidino, hexahydroazepino, morpholino or piperazino ring which may be optionally substituted by lower alkyl, aryl or aryl(lower)alkyl.
A is an alkylene chain of 2 to 4 carbon atoms optionally substituted by one or more lower alkyl groups,
R6 is a mono or bicyclic heteroaryl radical and R7 is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkyl(lower)alkyl, aryl, aryl(lower)alkyl, heteroaryl, heteroaryl(lower)alkyl, a group of formula -NR8R9 [where
R8 is hydrogen, lower alkyl, aryl or aryl(lower)alkyl and R9 is hydrogen, lower alkyl, -CO(lower)alkyl, aryl, COaryl, aryl(lower)alkyl, cycloalkyl or cycloalkyl(lower)alkyl or
R8 and R9 together with the nitrogen atom to which they are both attached represent a saturated heterocyclic ring which may contain a further hetero atom] or a group of formula OR 10[where R10 is lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, aryl, aryl(lower)alkyl, heteroaryl or heteroaryl(lower)alkyl].
2. A compound as claimed in claim 1 for use in the treatment of cancer.
3. The use of a compound as claimed in claim 1 in the manufacture of a medicament for the treatment of cancer.
4. A use as claimed in any one of the preceding claims wherein the compound is a compound of the formula II:
or the pharmaceutically acceptable acid addition salts thereof (where n, R, R1, R2, R3,
R4 and R5 are as defined in claim 1).
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9525239.1A GB9525239D0 (en) | 1995-12-09 | 1995-12-09 | Medical treatment |
Publications (3)
Publication Number | Publication Date |
---|---|
GB9625316D0 GB9625316D0 (en) | 1997-01-22 |
GB2307858A true GB2307858A (en) | 1997-06-11 |
GB2307858B GB2307858B (en) | 1999-07-28 |
Family
ID=10785215
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GBGB9525239.1A Pending GB9525239D0 (en) | 1995-12-09 | 1995-12-09 | Medical treatment |
GB9625316A Expired - Fee Related GB2307858B (en) | 1995-12-09 | 1996-12-05 | Medical treatment |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GBGB9525239.1A Pending GB9525239D0 (en) | 1995-12-09 | 1995-12-09 | Medical treatment |
Country Status (1)
Country | Link |
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GB (2) | GB9525239D0 (en) |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5527152A (en) * | 1978-08-18 | 1980-02-27 | Mitsui Toatsu Chem Inc | Immunizator containing 1-piperazinecarboxyamide derivative as effective ingredient |
GB2230780A (en) * | 1989-04-22 | 1990-10-31 | American Home Prod | Tertiary alkyl functionalised piperazine derivatives |
GB2230781A (en) * | 1989-04-22 | 1990-10-31 | Wyeth John & Brother Ltd | Piperazine derivatives as 5-ht(1a) antagonists |
GB2248836A (en) * | 1990-10-19 | 1992-04-22 | Wyeth John & Brother Ltd | Piperazine derivatives |
GB2255337A (en) * | 1991-05-02 | 1992-11-04 | Wyeth John & Brother Ltd | Piperazine derivatives |
GB2272155A (en) * | 1992-11-05 | 1994-05-11 | Wyeth John & Brother Ltd | Piperazine derivatives for treatment of cognitive disorders |
WO1995031988A1 (en) * | 1994-05-25 | 1995-11-30 | Smithkline Beecham P.L.C. | COMPOSITION CONTAINING 5HTIA and 5HTID ANTAGONISTS |
-
1995
- 1995-12-09 GB GBGB9525239.1A patent/GB9525239D0/en active Pending
-
1996
- 1996-12-05 GB GB9625316A patent/GB2307858B/en not_active Expired - Fee Related
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5527152A (en) * | 1978-08-18 | 1980-02-27 | Mitsui Toatsu Chem Inc | Immunizator containing 1-piperazinecarboxyamide derivative as effective ingredient |
GB2230780A (en) * | 1989-04-22 | 1990-10-31 | American Home Prod | Tertiary alkyl functionalised piperazine derivatives |
GB2230781A (en) * | 1989-04-22 | 1990-10-31 | Wyeth John & Brother Ltd | Piperazine derivatives as 5-ht(1a) antagonists |
GB2248836A (en) * | 1990-10-19 | 1992-04-22 | Wyeth John & Brother Ltd | Piperazine derivatives |
GB2255337A (en) * | 1991-05-02 | 1992-11-04 | Wyeth John & Brother Ltd | Piperazine derivatives |
GB2272155A (en) * | 1992-11-05 | 1994-05-11 | Wyeth John & Brother Ltd | Piperazine derivatives for treatment of cognitive disorders |
WO1995031988A1 (en) * | 1994-05-25 | 1995-11-30 | Smithkline Beecham P.L.C. | COMPOSITION CONTAINING 5HTIA and 5HTID ANTAGONISTS |
Non-Patent Citations (1)
Title |
---|
Chemical abstracts Acc. No. 93:210249 & JP550027152 (MITSUI TOATSU CHEM.) * |
Also Published As
Publication number | Publication date |
---|---|
GB2307858B (en) | 1999-07-28 |
GB9625316D0 (en) | 1997-01-22 |
GB9525239D0 (en) | 1996-02-07 |
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PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 20011205 |