CA2322136A1 - Glycine transport inhibitors - Google Patents
Glycine transport inhibitors Download PDFInfo
- Publication number
- CA2322136A1 CA2322136A1 CA002322136A CA2322136A CA2322136A1 CA 2322136 A1 CA2322136 A1 CA 2322136A1 CA 002322136 A CA002322136 A CA 002322136A CA 2322136 A CA2322136 A CA 2322136A CA 2322136 A1 CA2322136 A1 CA 2322136A1
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- CA
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- Prior art keywords
- formula
- 4alkyl
- radical
- hydrogen
- aryl
- 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.)
- Abandoned
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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- A—HUMAN NECESSITIES
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- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
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- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
- C07D211/56—Nitrogen atoms
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
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- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
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- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/86—Oxygen atoms
- C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
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- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
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- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
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Abstract
The present invention is concerned with the use of glycine transport inhibiting .alpha.,.alpha.-diphenyl-1-piperidinebutanamides for the preparation of medicaments for treating disorders of the central and peripheral nervous system, in particular psychoses, pain, epilepsy, neurodegenerative diseases (Alzheimer's disease), stroke, head trauma, multiple sclerosis and the like. The invention further comprises novel compounds, their preparation and their pharmaceutical forms.
Description
GLYCINE TRANSPORT INHIBITORS
The present invention is concerned with the use of glycine transport inhibiting a,a-di-phenyl-1-piperidinebutanamides for the preparation of medicaments for treating disorders of the central and peripheral nervous system, in particular psychoses, pain, epilepsy, neurodegenerative diseases (Alzheimer's disease), stroke, head trauma, multiple sclerosis and the like. The invention further comprises novel compounds, their preparation and their pharmaceutical forms.
N,N Dimethyl-a,a-Biphenyl-1-piperidinebutanamides such as 4-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl-a,a-Biphenyl-1-piperidinebutanamide (loperamide, ImodiumTM) are well-known anti-diarrhoea) products. These compounds, their activity and preparation were first disclosed in US-3,714,159.
The present invention is concerned with the use of glycine transport inhibiting compounds for the preparation of medicaments for treating disorders of the central and peripheral nervous system, said compounds having the formula x (I) N-R' the N-oxides, the stereochemically isomeric forms and the pharmaceutically acceptable addition salts thereof, wherein R' and R2 each independently represent hydrogen or C~_4alkyl;
X represents a radical of formula R
/C' R3 Ca); jC~ fib);
Rs wherein the dotted line represents an optional bond;
wR3 represents a radical of formula N
R6~~,,// \ i R8 ~N~ ~ ~ ~a_1) R~ (CHz)n R6 N~ j RS
\\-N ~ ~ (a-2) R~~
wherein R6 and R' each represent hydrogen or both may be taken together with the two carbon atoms to which they are attached to form a phenyl ring;
Rg represents hydrogen or halo;
n is 1 or 2;
R4 represents hydrogen, hydroxy, C,.4alkyloxy, C~_4alkyloxyC,_4alkyl, or aryl-C,_4alkyloxy;
RS represents diarylmethyloxyC,_4alkyl or a radical of formula N i a R
B ~\ ~ \~2 (b-1) y to N a4 ~ a3 _82~~ (b-2) Rti O ~ (b_4) w -B3 ~ ~ (b_3) N /
-N (b-6) Ria (b_5) N~ Ri6 Y~ ~Ri7 Y
-B~--C I \ (b-~) O
1$ N ~ -B$-C-R1g (b-8) R2a --.,-wN \ ~ (b_10) ~N
N~ (b-9) \
p R22 i N
O (b-11) -NH ~ ~ ~ (b_12) 123 H_ 'R2a WO 99/45011 PCTlEP99/OI308 ~N
(b-13) ~~ R2s i wherein B' represents -CH2, -CH(OH)-, -NH- , -CH2-NH_ or a direct bond;
B2 represents -NH-, -CH2- or a direct bond;
B3 represents -NR'2-, -CH2-, -C(=O)- or a direct bond;
B' represents -C'_4alkanediyl-NH- or -NH-C~_4aIkyl-;
B8 represents -NR'9-, -CH2- or -CH(aryl)-;
each Y independently represents O or S;
-a'=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH- (b-1-a) or -N=CH-N=CH- (b-1-b);
wherein a hydrogen atom in radical (b-1-a) may be replaced by hydroxy;
R9 represents C'_Qalkyl; or C'_4alkyl substituted with aryl, thienyl, furanyl, furanyl substituted with hydroxyCl_4alkyl, or thiazolyl;
R'° represents aryl, arylamino, C'_aalkylamino, C1_4alkylthio;
R" represents hydrogen, C,_4alkyl, halo or trifluoromethyl;
R12 represents hydrogen or C~_4alkylcarbonyl;
R'3 represents hydrogen, C~_4alkyl or aryl;
R'4 represents hydrogen or halo;
R'S and R'6 each independently represent hydrogen or aryl;
R" represents hydrogen or C,_4alkyl;
R'8 represents aryl, 10,11-dihydro-SH-dibenz[b,f]azepin-5-yl or C~_4alkyl optionally substituted with one or two substituents each independently selected from C3_~cycloalkyl and aryl;
R'9 represents hydrogen, C,_4alkylcarbonyl or diarylCl_4alkyl;
R2°, R2', R22 and R23 each independently represent hydrogen, C'_4alkyl or aryl;
R24 represents hydrogen or trifluoromethyl;
R25 represents hydrogen or halo; and in case RS represents a radical of formula (b-3), then R' may also be phenyl-C,_4alkylaminocarbonyl; and R4 and RS may be taken together to form a spiro radical of formula N-R~
(b_14, N
wherein R26 and R2' each independently represent hydrogen, C,_4alkyl, aryl or arylC,_4alkyl;
aryl represents phenyl, or phenyl substituted with 1 or 2 substituents independently selected from C1_4alkyl, halo, trifluoromethyl, hydroxy and C~_4alkyloxy.
The present invention also relates to a method of treating warm-blooded animals suffering from disorders of the central and peripheral nervous system, in particular psychoses, pain, epilepsy, neurodegenerative diseases (Alzheimer's disease), stroke, head trauma, multiple sclerosis and the like. Said method comprises the administration of a therapeutically effective amount of a compound of formula (I) or a N
oxide form, a pharmaceutically acceptable acid or base addition salt or a stereochemically isomeric form thereof in admixture with a pharmaceutical carrier.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C3_7cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C1_4alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyl and the like;
C1_4alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, 1;1-methanediyl, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,2-propanediyl, 2,3-butanediyl and the like.
The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic base and acid addition salt forms which the compounds of formula (I) are able to form. The acid addition salt form of a compound of formula (I) that occurs in its free form as a base can be obtained by treating said free base form with an appropriate acid such as an inorganic acid, for example, hydrohalic acid, e.g. hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like acids; or an organic acid, such as, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, oxalic, malonic, succinic, malefic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicyIic, pamoic and the like acids.
The present invention is concerned with the use of glycine transport inhibiting a,a-di-phenyl-1-piperidinebutanamides for the preparation of medicaments for treating disorders of the central and peripheral nervous system, in particular psychoses, pain, epilepsy, neurodegenerative diseases (Alzheimer's disease), stroke, head trauma, multiple sclerosis and the like. The invention further comprises novel compounds, their preparation and their pharmaceutical forms.
N,N Dimethyl-a,a-Biphenyl-1-piperidinebutanamides such as 4-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl-a,a-Biphenyl-1-piperidinebutanamide (loperamide, ImodiumTM) are well-known anti-diarrhoea) products. These compounds, their activity and preparation were first disclosed in US-3,714,159.
The present invention is concerned with the use of glycine transport inhibiting compounds for the preparation of medicaments for treating disorders of the central and peripheral nervous system, said compounds having the formula x (I) N-R' the N-oxides, the stereochemically isomeric forms and the pharmaceutically acceptable addition salts thereof, wherein R' and R2 each independently represent hydrogen or C~_4alkyl;
X represents a radical of formula R
/C' R3 Ca); jC~ fib);
Rs wherein the dotted line represents an optional bond;
wR3 represents a radical of formula N
R6~~,,// \ i R8 ~N~ ~ ~ ~a_1) R~ (CHz)n R6 N~ j RS
\\-N ~ ~ (a-2) R~~
wherein R6 and R' each represent hydrogen or both may be taken together with the two carbon atoms to which they are attached to form a phenyl ring;
Rg represents hydrogen or halo;
n is 1 or 2;
R4 represents hydrogen, hydroxy, C,.4alkyloxy, C~_4alkyloxyC,_4alkyl, or aryl-C,_4alkyloxy;
RS represents diarylmethyloxyC,_4alkyl or a radical of formula N i a R
B ~\ ~ \~2 (b-1) y to N a4 ~ a3 _82~~ (b-2) Rti O ~ (b_4) w -B3 ~ ~ (b_3) N /
-N (b-6) Ria (b_5) N~ Ri6 Y~ ~Ri7 Y
-B~--C I \ (b-~) O
1$ N ~ -B$-C-R1g (b-8) R2a --.,-wN \ ~ (b_10) ~N
N~ (b-9) \
p R22 i N
O (b-11) -NH ~ ~ ~ (b_12) 123 H_ 'R2a WO 99/45011 PCTlEP99/OI308 ~N
(b-13) ~~ R2s i wherein B' represents -CH2, -CH(OH)-, -NH- , -CH2-NH_ or a direct bond;
B2 represents -NH-, -CH2- or a direct bond;
B3 represents -NR'2-, -CH2-, -C(=O)- or a direct bond;
B' represents -C'_4alkanediyl-NH- or -NH-C~_4aIkyl-;
B8 represents -NR'9-, -CH2- or -CH(aryl)-;
each Y independently represents O or S;
-a'=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH- (b-1-a) or -N=CH-N=CH- (b-1-b);
wherein a hydrogen atom in radical (b-1-a) may be replaced by hydroxy;
R9 represents C'_Qalkyl; or C'_4alkyl substituted with aryl, thienyl, furanyl, furanyl substituted with hydroxyCl_4alkyl, or thiazolyl;
R'° represents aryl, arylamino, C'_aalkylamino, C1_4alkylthio;
R" represents hydrogen, C,_4alkyl, halo or trifluoromethyl;
R12 represents hydrogen or C~_4alkylcarbonyl;
R'3 represents hydrogen, C~_4alkyl or aryl;
R'4 represents hydrogen or halo;
R'S and R'6 each independently represent hydrogen or aryl;
R" represents hydrogen or C,_4alkyl;
R'8 represents aryl, 10,11-dihydro-SH-dibenz[b,f]azepin-5-yl or C~_4alkyl optionally substituted with one or two substituents each independently selected from C3_~cycloalkyl and aryl;
R'9 represents hydrogen, C,_4alkylcarbonyl or diarylCl_4alkyl;
R2°, R2', R22 and R23 each independently represent hydrogen, C'_4alkyl or aryl;
R24 represents hydrogen or trifluoromethyl;
R25 represents hydrogen or halo; and in case RS represents a radical of formula (b-3), then R' may also be phenyl-C,_4alkylaminocarbonyl; and R4 and RS may be taken together to form a spiro radical of formula N-R~
(b_14, N
wherein R26 and R2' each independently represent hydrogen, C,_4alkyl, aryl or arylC,_4alkyl;
aryl represents phenyl, or phenyl substituted with 1 or 2 substituents independently selected from C1_4alkyl, halo, trifluoromethyl, hydroxy and C~_4alkyloxy.
The present invention also relates to a method of treating warm-blooded animals suffering from disorders of the central and peripheral nervous system, in particular psychoses, pain, epilepsy, neurodegenerative diseases (Alzheimer's disease), stroke, head trauma, multiple sclerosis and the like. Said method comprises the administration of a therapeutically effective amount of a compound of formula (I) or a N
oxide form, a pharmaceutically acceptable acid or base addition salt or a stereochemically isomeric form thereof in admixture with a pharmaceutical carrier.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C3_7cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C1_4alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyl and the like;
C1_4alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, 1;1-methanediyl, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,2-propanediyl, 2,3-butanediyl and the like.
The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic base and acid addition salt forms which the compounds of formula (I) are able to form. The acid addition salt form of a compound of formula (I) that occurs in its free form as a base can be obtained by treating said free base form with an appropriate acid such as an inorganic acid, for example, hydrohalic acid, e.g. hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like acids; or an organic acid, such as, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, oxalic, malonic, succinic, malefic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicyIic, pamoic and the like acids.
The compounds of formula (I) containing acidic protons may be converted into their therapeutically active non-toxic base, i.e. metal or amine, addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
Conversely said salt foams can be converted into the free forms by treatment with an appropriate base or acid.
The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like.
The N-oxide forms of the compounds of formula (I) are meant to comprise those com-pounds of formula (I) wherein the piperidine nitrogen atom is oxidized to the N oxide.
The term "stereochemically isomeric forms" as used herein defines all the possible stereoisomeric forms of the compounds of formula (I). Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture, and in particular the racemic mixture, of all possible stereochemically isomeric forms, said mixture containing all diastereomers and enantiomers of the basic molecular structure.
Stereochemically isomeric forms of the compounds of formula (I) and mixtures of such forms are obviously intended to be encompassed by formula (I).
In particular, the compounds of formula (I) and some of their intermediates have at least one stereogenic center in their structure. This stereogenic center may be present in a R
or a S configuration, said R and S notation is used in correspondance with the rules described in Pure Appl. Chem., 1976, 45, 11-30.
Some of the compounds of formula (I) may also exist in their tautomeric forms.
Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
Whenever used hereinafter, the term compounds of formula (I) is meant to include also the N-oxides, the pharmaceutically acceptable additian salts and all stereoisomeric forms.
Conversely said salt foams can be converted into the free forms by treatment with an appropriate base or acid.
The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like.
The N-oxide forms of the compounds of formula (I) are meant to comprise those com-pounds of formula (I) wherein the piperidine nitrogen atom is oxidized to the N oxide.
The term "stereochemically isomeric forms" as used herein defines all the possible stereoisomeric forms of the compounds of formula (I). Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture, and in particular the racemic mixture, of all possible stereochemically isomeric forms, said mixture containing all diastereomers and enantiomers of the basic molecular structure.
Stereochemically isomeric forms of the compounds of formula (I) and mixtures of such forms are obviously intended to be encompassed by formula (I).
In particular, the compounds of formula (I) and some of their intermediates have at least one stereogenic center in their structure. This stereogenic center may be present in a R
or a S configuration, said R and S notation is used in correspondance with the rules described in Pure Appl. Chem., 1976, 45, 11-30.
Some of the compounds of formula (I) may also exist in their tautomeric forms.
Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
Whenever used hereinafter, the term compounds of formula (I) is meant to include also the N-oxides, the pharmaceutically acceptable additian salts and all stereoisomeric forms.
The present compounds of formula (I) are deemed novel provided that when R4 is hydrogen and RS is a radical of formula (b-1) wherein B~ is -CH2- and R9 is 4-fluorohenzyl, then -a'=a2-a3=a4- is other than -CH=CH-CH=CH-; and when R4 is hydrogen and RS is a radical of formula (b-1) wherein B~ is -NH- and R9 is 4-methoxybenzyl, then -a'=a2-a3=a4- is other than -CH=N-CH=N-. The present invention also relates to said novel compounds of formula (I) for use as a medicine.
Suitably, RS is diarylmethyloxyC,.4alkyl or a radical of formula (b-2), (b-3), (b-4), (b-5), (b-6), (b-7), (b-8), (b-9), (b-10), {b-11), (b-12) or (b-13); or RS may be taken together with R4 to form a spiro radical of formula (b-14).
An interesting group of compounds are those compounds of formula (I) wherein R' and R2 are methyl.
Particular compounds are those compounds of formula (I) wherein X represents a radical of formula (a), more in particular, a radical of formula (a) wherein R6 and R' are taken together with the two carbon atoms to which they are attached to form a phenyl ring.
Other particular compounds are those compounds of formula (I) wherein X
represents a radical of formula (b) wherein RS is a radical of formula (b-1), and preferably, R9 represents C,_4alkyl substituted with aryl, especially wherein R9 is 4-fluorobenzyl.
Yet other particular compounds are those compounds of formula (I) wherein X
represents a radical of formula (b) wherein R5 is a radical of formula (b-2), and preferably Y is S.
Preferred compounds are 4-( 11,12-dihydro-6H-benzimidazo[2,1-b] [3 ]benzazepin-6-yl)-N,N-dimethyl-a,a-diphenyl-i-piperidinebutanamide;
4-[[1-[{4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]hydroxymethyl)-N,N-dimethyl-a,a-diphenyl-1-piperidinebutanamide; the N-oxides, the stereochemically isomeric forms and the pharmaceutically acceptable addition salts thereof.
In general, the compounds of formula (I) can be prepared according to reaction procedures described in US 3,714,159, US-4,695,575 and US-5,008,268, more in particular, by reacting an intermediate of formula (II) wherein 'W is an appropriate counter ion such as, for example, a halogen, or a functional derivative thereof with an intermediate of formula (III).
WO 99/45011 PG"C/EP99/01308 _'7_ -~~- (I) (II}
(an Said reaction may be performed in a reaction-inert solvent such as, for example, methylisobutyl keton, N,N-dimethylacetamide or N,N dimethylformamide, in the presence of a suitable base such as, for example, sodium carbonate, sodium bicarbonate or triethylamine, and optionally in the presence of potassium iodide.
In this and the following preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, distillation, IO trituration and chromatography.
The compounds of formula (I) can also be converted into each other following art-known procedures of functional group transformation.
The compounds of formula (I) may also be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with 3-phenyl-2-(phenylsulfonyl)oxaziridine or with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g.
sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. t-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydro-carbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.
dichloromethane, and mixtures of such solvents.
Some of the compounds of formula (I) and some of the intermediates in the present in-vention may contain an asymmetric carbon atom. Pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by the application of art-known procedures. For example, diastereoisomers can be separated by physical _g-methods such as selective crystallization or chromatographic techniques, e.g, counter current distribution, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts S or compounds; then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallization or chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting said separated diastereomeric salts or compounds into the corresponding enantiomers. Pure stereochemically isomeric forms may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intervening reactions occur stereospecifically.
An alternative manner of separating the enantiomeric forms of the compounds of formula (I) and intermediates involves liquid chromatography, in particular liquid 1S chromatography using a chiral stationary phase.
Some of the intermediates and starting materials are known compounds and may be commercially available or may be prepared according to art-known procedures.
Glycine is an amino acid neurotransmitter in the central and peripheral nervous system, both at inhibitory and excitatory synapses. These distinct functions of glycine are mediated by two types of receptor, each of which is associated with a different class of glycine transporter. The inhibitory actions of glycine are mediated by glycine receptors that are sensitive to the convulsant alkaloid strychnine, and are therefore referred to as 2S 'strychnine-sensitive.' Strychnine-sensitive glycine receptors are found predominantly in the spinal cord and brainstem.
Glycine functions in excitatory transmission by modulating the actions of glutamate, the major excitatory neurotransmitter in the nervous system (Johnson and Ascher, Nature, 325, S29-S31 (1987); Fletcher et al., Glvcine Transmission, (Otterson and Storm-Mathisen, eds., 1990), pp. 193-219). Specifically, glycine is an obligatory co-agonist at the class of glutamate receptor termed N-methyl-D-aspartate (NMDA) receptor. NMDA receptors are widely distributed throughout the brain, with a particularly high density in the cerebral cortex and hippocampal formation.
Transporters take up neurotransmitter from the synapse, thereby regulating the concentration and term of neurotransmitter in the synapse, which together determine the magnitude of synaptic transmission. By preventing the spread of neurotransmitter to neighboring synapses, trarlsporters maintain the fidelity of synaptic transmission. Last, by re-uptake of released transmitter into the presynaptic terminal, transporters allow for transmitter reutilization. Neurotransmitter transport is dependent on extracellular sodium and the voltage difference across the membrane. Under specific conditions, for example during a seizure, transporters can function in reverse, releasing neurotransmitter in a calciumindependent non-exocytotic manner (Attwell et al., Neuron, 11, 401-407 (1993)). Modulation of neurotransmitter transporters thus provides a means for modifying synaptic activity, which provides useful therapy for the treatment of disturbances of the central and peripheral nervous system.
Molecular cloning has revealed the existence of two classes of glycine transporters, termed GIyT-1 and GIyT-2. GIyT-1 is found predominantly in the forebrain, and its distribution corresponds to that of glutamatergic pathways and NMDA receptors (Smith, et al., Neuron. 8, 927-935 (1992)). At least three splice variants of GIyT-1 are known, namely GIyT-la, GIyT-lb and GIyT-lc (Kim, et al., Molecular Pharmacolo y, 45, 617 (1994)), each of which displays a unique distribution in the brain and peripheral tissues. GIyT-2, in contrast, is found predominantly in the brainstem and spinal cord, and its distribution corresponds closely to that of strychnine-sensitive glycine receptors (Liu et al., J Biological Chemistry , 268,. 22802-22808 (1993); Jursky and Nelson, Neurochemistry, 64, 10261033 (1995)). Thus, one can expect that by regulating the synaptic levels of glycine, GIyT-1 and GIyT-2 selectively modulate the activity of NMDA receptors and strychnine-sensitive glycine receptors, respectively.
Compounds that inhibit or activate glycine transporters would thus be expected to alter receptor function, and provide therapeutic benefits in a variety of disease states. Thus, inhibition of GIyT-2 could be used to diminish the activity of neurons having strychnine-sensitive glycine receptors via increasing synaptic levels of glycine, and so diminish the transmission of pain-related (i.e., nociceptive) information in the spinal cord, which has been shown to be mediated by these receptors. Yaksh, Pain, 37, 111-123 (1989). Additionally, enhancing inhibitory glycinergic transmission through strychnine-sensitive glycine receptors in the spinal cord can be used to decrease muscle hyperactivity, which is useful in treating diseases or conditions associated with increased muscle contraction, such as spasticity, myacIonus, and epilepsy {Truong et al., Movement Disorders, 3 , 77-87 (1988); Becker, I~ASEB J, 4 2767-2774 (1990)).
Spasticity that can be treated via modulation of glycine receptors is associated with epilepsy, stroke, head trauma, multiple sclerosis, spinal cord injury, dystonia, and other conditions of illness and injury of the nervous system.
NMDA receptors are involved in memory and Teaming (Rison and Stanton, Neurosci.
Biobehav. Rev., 19, 533 552 (1995); Danysz at al., Behavioral Pharmacol , 6, (1995)); and decreased function of NMDA-mediated neurotransmission appears to contribute to the symptoms of schizophrenia (Olney and Farber, Archives General Psvchiatrv, 52, 998-1007 (1996). Thus, agents that inhibit GIyT-1 and thereby increase glycine activation of NMDA receptors can be used as novel antipsychotics and anti-dementia agents, and to treat other diseases in which cognitive processes are impaired, such as attention deficit disorders and organic brain syndromes.
Conversely, over-activation of NMDA receptors has been implicated in a number of disease states, in particular the neuronal death associated with stroke, head trauma and possibly neurodegenerative diseases, such as Alzheimer's disease, mufti-infarct dementia, AIDS
dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or other conditions in which neuronal cell death occurs. Coyle & Puttfarcken, Science, 262, 689-695 (1993); Lipton and- Rosenberg, New Engl. J. of Medicine, 330, 613-(1993); Choi, Neuron 1, 623-634 (1988). Thus, phamlacological agents that increase the activity of GIyT-1 will result in decreased glycine-activation of NMDA
receptors, which activity can be used to treat these and related disease states.
Similarly, drugs that directly block the glycine site on the NMDA receptors can be used to treat these and related disease states.
For administration purposes, the subject compounds may be formulated into various pharmaceutical compositions comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a novel compound of formula (I). To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, in addition salx or in free acid or base form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid earners such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid WO 99/~t5011 PCT/EP99/01308 pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable solutions containing compounds of formula (I) may be formulated in an oil for prolonged action.
Appropriate oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soy bean oil, synthetic glycerol esters of long chain fatty acids and mixtures of these and other oils. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment. Addition salts of (I) due to their increased water solubility over the corresponding free base or free acid form, are obviously more suitable in the preparation of aqueous compositions.
It is especially advantageous to formulate the aforementioned pharmaceutical composi-tions in dosage unit form for ease of administration and uniformity of dosage.
Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with the required pharmaceutical Garner. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
The following examples are intended to illustrate the present invention.
Exverimental part Example A.1 A mixture of dimethyl (tetrahydro-3,3-diphenyl-2-furylidene) ammonium bromide (0.01 mol), prepared as described in US 3,714,159, (~)-4-(11,12-dihydro-6H
benzimidazo[2,1-b][3]benzazepin-6-yl)-piperidine (0.01 mol), Na2CO3 (0.01 mol) and KI (10 mg) in methyl isobutyl keton (200mL) was stirred and refluxed overnight. The solvent was evaporated and the residue taken up in water/CH2Cl2. The organic layer was separated and the water layer was extracted again with CH2C12. The combined organic layers were dried, filtered and the solvent evaporated. The residue was purified on a glass filter over silica gel (eluent : CH2Cl2/CHaOH 95/S to 90/10). The pure fractions were collected and evaporated. The residue was crystallized from CH3CN, yielding 0.88g (15%) of (~)-4-(11,12-dihydro-6H-benzimidazo[2,1-b][3]benzazepin-6-yl)-N,N dimethyl-a,a-diphenyl-1-piperidinebutanamide (comp. I; mp. 255.3 °C).
Example A.2 To a stirred mixture of 4-(3-bromo-2-oxopropyl)-N,N-dimethyl-a,a-diphenyl-1-piperidinebutanamide monohydrobromide (13 g) in methanol (80 ml) was added (2,6-dimethylphenyl)thiourea (4.1 g) at 70 °C. Stirnng was continued for 1 hour at reflux temperature. The solvent was evaporated and the residue was taken up in water.
Potassium carbonate was added untill a pH of about 9 and the mixture was extracted with ethylacetate. The organic phase was purified by acid base extraction, dried, filtered and the solvent evaporated. The residue was crystallized from methanol. The precipitate was filtered off, washed and dried, yielding 6.7 g (52 %) of 4-[[2-[[2,6-dimethylphenyl)amino]-4-thiazolyl]methyl)-N,N-dimethyl-a,a-diphenyl-1-piperidine-butanamide (comp. 47; mp. 210.5 °C).
In an analogous way were prepared 4-[[2-[[2,6-dichlorophenyl)amino]-4-thiazolyl]methyl]-N,N-dimethyl-a,a-diphenyl-1-piperidinebutanamide (comp. 48; mp. 207.0 °C);
N,N-dimethyl-4-[[2-(methylamino)-4-thiazolyl]methyl]-a,a-diphenyl-1-piperidine-butanamide (comp. 49; mp. 188.3 °C).
Example A.3 To a stirred mixture of NaH (78 % dispersion; 0.55 g) in 1,4-dioxane (50 ml) was added 1-(4-fluorophenyl)-N,N dimethyl-4-oxo-a,a-Biphenyl-1,3,8-triazaspiro[4,5]-decane-8-butanamide (7.7 g). After stirring for 1 hour at room temperature, the mixture was heated to 60 °C and (chloromethyl)benzene (2.3 g) was added.
Stirnng was continued overnight at 60 °C. the reaction mixture was poured out onto water and the mixture was extracted with CHCl3. The extract was washed with water, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel using a mixture of CHC13 and 3 % methanol, saturated with gaseous ammonia, as eluent.The pure fractions were collected and the solvent evaporated. The residue was triturated in n-hexane. The precipitate was filtered off and dried, yielding 2 g of 1-(4-fluorophenyl)-N,N-dimethyl-4-oxo-a,a-Biphenyl-3-phenylmethyl-1,3,8-triazaspiro[4,5]decane-8-butanamide (comp. 50; mp. 139.8 °C).
Tables 1 and 2 list compounds which were prepared according to example A.1.
Some compounds were prepared using a different base and/or solvent as regards the ones used in example A.I. Also, some compounds were prepared without using KI. The reaction conditions are mentioned in column "reaction conditions" in tables 1 and 2. In said column, MIK means methylisobutyl keton, DMA means N,N dimethylacetamide and DMF means N,N-dimethylformamide.
Table 1 °' RS R4 Reaction conditions Physical properties base / KI I solvent meltin oint : m . in °C
N
1 ~ ~ N -' H Na2C03 I KI / MIK mp. 255.3°C
2 <'N~~ I ~ H Na2C03 / KI / DMA mp. 173.7°C
~N
Br N
3 ~ / N ~ ~ H Na2C0.3 / KI / MIK mp. 210.6°C
_.
H Na2C0~ I - I MIK
~N _ H Na2C03 / - / DMF mp. 239.0°C;
Ntt~ \ /
HZO (1:1); HCl (1:2) 6 ~ ~ H Et3N / - / DMF mp. 168.8°C; HBr ( 1:2) ~~s N
,7 N
H Na2C03 / - / MIK mp. 196.4°C
U
°' RS R' Reaction conditions Physical properties vo. base ! KI / solvent meltin oint : m . in °C
s ~ "~ ~ ~ ~=QH
N H NazC03 I - I MIK mp. 128.9°C; H20 (1:1) -NH--<
N
H
H NazC03 I KI I M1K mp. 184.5°C
N ~ OH
-CHZ
~N I ~
°
10 ~ Hz \ ~ H NazCO 3 / KI / MIK mp. 161.4°C
N
CH2~~
N
11 CH, ~ ~ F
OH NazCO3 I KI I MIK mp. 170.5°C
N
-CH2 \\
N /
12 -cHZ / \ cH3 OH NazC03 I KI I MIK mp. 135°C
13 / \ c~ o-~'~'x Et3N / - / DMA mp. 161.3°C;
o HCl ( 1:1 ); H20 ( 1:1 ) _ II
14 CH-C-CHz-CH3 H NazC03 / - / MIK mp. 160.7°C;
ethanedioate (3:2) 15 ~ ~ ~ H NazC03 / KI / MIK mp. 265.4°C; HBr(2:1) o H NazC03 I - I MIK mp. 139.1 °C
i Hy-CH3 17 -NH N \ H NazC03 I KI I MIK mp. 199.4°C
---y ''~l N /
O _ 18 -c-NH-cHZ ~ ~ -~ / ~ NazC03 I KI I MIK mp. 111.5-145°C;
_ H20 (2:1) ' ~ / NazCO~ I - I MIK mp. 188.8°C
- -I S-°' RS R' Reaction conditions Physical properties ~o. base l KI I solvent melon oint : m . in °C
20 -o-~-~H
Na2C03 / KI / MIK mp. 111.9°C ; HCl (2:1) II
H Na2C03 / - / MIK mp. 202-205°C
H
\ N
22 -NH~ ~>'-oF3 H Na2CO3 / KI / DMF mp. 192.4°C
N
\N~ N
23 / ~ H Na2CO 3 / KI / MIK mp. IS6.1°C
Ci 24 ~ I H I Na2CO3 I KI / MIK , mp. 208.9°C
(1:1) s \
25 '°HZ-~~N ~ , OH Na2C03 I - I MIK mp. 257.4°C
i o~ H NaZCO~ / - / MIK mp. 176.2°C;
E)-2-butenedioate (I:1) CH,_ 27 ~ N H NazC03 / - / MIK mp. 142.7°C
N ~ /
28 / \ H Na2C03 I - I MIK mp. 198.0°C;
ethanedioate (I:I) Cl I -O C
29 ~ H Na2C0~ / KI / MIK mp. 133.1-135.1 °C;
ethanedioate (2:S) S
30 -~Z~N ~ / H NaHC03 / - / DMF m . 14 ° .
p 8.7 C, s~ ethanedioate (1:2) ~~S-CH3 31 -~HZ ~ ~~N H NaHC03 / - I DMF mp. 121.8°C
' Rs R4 Reaction conditionsPhysical properties vo. base / KI / meltin oint :
c~ solvent m . in C
32 s H NaHC03 / - mp. 251.0C
/ DMF
cl 33 cHZ ~ / F OH Et3N / - / m . 1 DMF p 83.3 C
N /
~3 N~-r ~ / H NaHC03 / - mp. 257.3C
/ DMF
N
~3 35 i Z ~ / F H Et3N / - / m . 136.
DMF p S C, N \ ethanedioate {
'IH~ 1:3) OH N /
36 cHz ~
I H Na2C03 / - mp. 207.4C;
I DMF
N \ ethanedioate ( ~ 1:2) N
37 cHz ~ / F OCH3 Na2C03 / - m . 22 . .
I / DMF p 0 1 C, N ~ (E)-2-butenedioate {1:1) N /
CI
38 s ri,., ~ / OH NaHCO 3 / - mp. 183.7C;
/ DMF
N CI (2:1); ethanol (1:1) cl 39 s -N,j ~ / OH NaHC03 I - mp. 198.7C
I DMF
N
cx, S
~~
40 cH2 H Na2C03 / - p. 183.9C
m / DMA
N \
~~2 S
41 CHz I ~ ~
H NazC03 / - mp. 201.4C;
/ DMA
'CH N \ (E)-2-butenedioate (2:3) N /
' R5 R Reaction conditionsPhysical properties ~o. base / KI / meltin oint :
solvent m . in C
s 42 H Na2C03 / - mp. 177.8C;
cH, N ~ / DMF
(Z)-2-butenedioate (1:2) _ ~
43 ~ ~ ~ ~
H Na2CO3 / KI m .
/ DMF p 190.5 C
_ 53 i 2 ~ / F OH Na2C03 / - m . 164.
/ MIK p SC
N
-CHZ_NH
~
N
O
54 -~c-cH' CHZ-O-CH3Na2CO3 / - mp. 155.4C; HCI
/ MIK (1:1) Table 2 f/ ~ p /CH3 N
\CH3 \CH~-CHZ_N\~R3 o.
R3 Reaction conditionsPhysical properties vo. base / KI I melon oint : m solvent . in C
N
~ Na2C03 l KI m N p.
f .
;
r,... \ (E)-2-butenedioate ( 1:1 ) N
45 CN i Na2C03 / KI mp. 174.5C
-, \ / MIK
Also prepared according to example A.1 but without using KI was 1-(5-chloro-2-methyl-phenyl)-N,N-dimethyl-4-oxo-a,a-Biphenyl-1,3,8-triazaspiro[4,5]decane-8-butanamide (comp. 46; mp. 175.7°C).
Pharmacological example Example B.l: Assay of transport via GIyTI transnorters Subconfluent HEK 293 -GIyTl cells (i.e. a cell line which stably expresses human glycine transporter 1) were seeded in Cytostar-T plates at a concentration of 50,000 cells per well in 100 pl DMEM medium (Dulbecco's Modified Eagle Medium supplemented with 10% foetal bovine serum, 1 mM Na-pyruvate, 2 mM glutamine, WO 99/45011 PC"T/EP99/01308 U penicillin/ml and 0.1 mg/ml streptomycin). The cells were incubated for 48 hours at 37°C, 5% C02, 95% humidity.
On day 3, the cells were washed using a Tecan PW96 microprocessor controlled washer S designed to wash all 96 wells of a microplate simultaneously with uptake buffer (25 mM Hepes, 5.4 mM K-gluconate, 1.8 mM Ca-gluconate, 0.8 mM MgS04, 140 mM
NaCI, S mM glucose, 5 mM alanine, adjusted to pH 7.5 with 2M Tris). The Tecan PW96 was programmed to wash the cells five times leaving 75 pI in each well.
The test compounds were dissolved at different concentrations in the micromolar range in DMSO. 1 lrl Test solution was added to each well and the cells were incubated for 5' to 10' at ambient temperature. Then there was added 25 ~tl 30 ~.M
[U'4C]glycine diluted in uptake buffer. The cells were incubated for 1 hour at ambient temperature.
The plates were then sealed and [U'4C]glycine uptake was determined on a Packard microplate scintillation counter (TopCount). From the results obtained for the various concentrations of each test drug, the concentration giving 50 % inhibition {ICso) of glycine uptake was calculated. Calculated data for the test compounds according to the instant invention are shown in table 3 as pICso values (negative log values of the ICso).
Compound 51 being 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-N,N-dimethyl-a,a-diphenyl-1-piperidinebutanamide as disclosed in US-4,695,575 and compound 52 being 4-[[9-[(4-methoxyphenyl)methyl]-9H-purin-8-yl]amino]-N,N-dimethyl-a,a-diphenyl-1-piperidinebutanamide {E)-2-butenedioate (2:5) as disclosed in US-5,008,268 were also tested.
Table 3 Comp. PICso Comp. PICso No. No.
1 7.28 28 6.56 2 6.80 29 6.10 3 6.77 30 6.63 4 6.49 31 6.17 6.43 32 6.12 6 6~1~ 33 6.21 7 6.16 34 6.35 8 6.05 35 7.22 9 6.13 36 6.25 10 6.62 37 6.90 11 6.89 38 6.04 12 6.15 39 6.23 Comp. PICso Comp. PICso No. No.
Suitably, RS is diarylmethyloxyC,.4alkyl or a radical of formula (b-2), (b-3), (b-4), (b-5), (b-6), (b-7), (b-8), (b-9), (b-10), {b-11), (b-12) or (b-13); or RS may be taken together with R4 to form a spiro radical of formula (b-14).
An interesting group of compounds are those compounds of formula (I) wherein R' and R2 are methyl.
Particular compounds are those compounds of formula (I) wherein X represents a radical of formula (a), more in particular, a radical of formula (a) wherein R6 and R' are taken together with the two carbon atoms to which they are attached to form a phenyl ring.
Other particular compounds are those compounds of formula (I) wherein X
represents a radical of formula (b) wherein RS is a radical of formula (b-1), and preferably, R9 represents C,_4alkyl substituted with aryl, especially wherein R9 is 4-fluorobenzyl.
Yet other particular compounds are those compounds of formula (I) wherein X
represents a radical of formula (b) wherein R5 is a radical of formula (b-2), and preferably Y is S.
Preferred compounds are 4-( 11,12-dihydro-6H-benzimidazo[2,1-b] [3 ]benzazepin-6-yl)-N,N-dimethyl-a,a-diphenyl-i-piperidinebutanamide;
4-[[1-[{4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]hydroxymethyl)-N,N-dimethyl-a,a-diphenyl-1-piperidinebutanamide; the N-oxides, the stereochemically isomeric forms and the pharmaceutically acceptable addition salts thereof.
In general, the compounds of formula (I) can be prepared according to reaction procedures described in US 3,714,159, US-4,695,575 and US-5,008,268, more in particular, by reacting an intermediate of formula (II) wherein 'W is an appropriate counter ion such as, for example, a halogen, or a functional derivative thereof with an intermediate of formula (III).
WO 99/45011 PG"C/EP99/01308 _'7_ -~~- (I) (II}
(an Said reaction may be performed in a reaction-inert solvent such as, for example, methylisobutyl keton, N,N-dimethylacetamide or N,N dimethylformamide, in the presence of a suitable base such as, for example, sodium carbonate, sodium bicarbonate or triethylamine, and optionally in the presence of potassium iodide.
In this and the following preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, distillation, IO trituration and chromatography.
The compounds of formula (I) can also be converted into each other following art-known procedures of functional group transformation.
The compounds of formula (I) may also be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with 3-phenyl-2-(phenylsulfonyl)oxaziridine or with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g.
sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. t-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydro-carbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.
dichloromethane, and mixtures of such solvents.
Some of the compounds of formula (I) and some of the intermediates in the present in-vention may contain an asymmetric carbon atom. Pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by the application of art-known procedures. For example, diastereoisomers can be separated by physical _g-methods such as selective crystallization or chromatographic techniques, e.g, counter current distribution, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts S or compounds; then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallization or chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting said separated diastereomeric salts or compounds into the corresponding enantiomers. Pure stereochemically isomeric forms may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intervening reactions occur stereospecifically.
An alternative manner of separating the enantiomeric forms of the compounds of formula (I) and intermediates involves liquid chromatography, in particular liquid 1S chromatography using a chiral stationary phase.
Some of the intermediates and starting materials are known compounds and may be commercially available or may be prepared according to art-known procedures.
Glycine is an amino acid neurotransmitter in the central and peripheral nervous system, both at inhibitory and excitatory synapses. These distinct functions of glycine are mediated by two types of receptor, each of which is associated with a different class of glycine transporter. The inhibitory actions of glycine are mediated by glycine receptors that are sensitive to the convulsant alkaloid strychnine, and are therefore referred to as 2S 'strychnine-sensitive.' Strychnine-sensitive glycine receptors are found predominantly in the spinal cord and brainstem.
Glycine functions in excitatory transmission by modulating the actions of glutamate, the major excitatory neurotransmitter in the nervous system (Johnson and Ascher, Nature, 325, S29-S31 (1987); Fletcher et al., Glvcine Transmission, (Otterson and Storm-Mathisen, eds., 1990), pp. 193-219). Specifically, glycine is an obligatory co-agonist at the class of glutamate receptor termed N-methyl-D-aspartate (NMDA) receptor. NMDA receptors are widely distributed throughout the brain, with a particularly high density in the cerebral cortex and hippocampal formation.
Transporters take up neurotransmitter from the synapse, thereby regulating the concentration and term of neurotransmitter in the synapse, which together determine the magnitude of synaptic transmission. By preventing the spread of neurotransmitter to neighboring synapses, trarlsporters maintain the fidelity of synaptic transmission. Last, by re-uptake of released transmitter into the presynaptic terminal, transporters allow for transmitter reutilization. Neurotransmitter transport is dependent on extracellular sodium and the voltage difference across the membrane. Under specific conditions, for example during a seizure, transporters can function in reverse, releasing neurotransmitter in a calciumindependent non-exocytotic manner (Attwell et al., Neuron, 11, 401-407 (1993)). Modulation of neurotransmitter transporters thus provides a means for modifying synaptic activity, which provides useful therapy for the treatment of disturbances of the central and peripheral nervous system.
Molecular cloning has revealed the existence of two classes of glycine transporters, termed GIyT-1 and GIyT-2. GIyT-1 is found predominantly in the forebrain, and its distribution corresponds to that of glutamatergic pathways and NMDA receptors (Smith, et al., Neuron. 8, 927-935 (1992)). At least three splice variants of GIyT-1 are known, namely GIyT-la, GIyT-lb and GIyT-lc (Kim, et al., Molecular Pharmacolo y, 45, 617 (1994)), each of which displays a unique distribution in the brain and peripheral tissues. GIyT-2, in contrast, is found predominantly in the brainstem and spinal cord, and its distribution corresponds closely to that of strychnine-sensitive glycine receptors (Liu et al., J Biological Chemistry , 268,. 22802-22808 (1993); Jursky and Nelson, Neurochemistry, 64, 10261033 (1995)). Thus, one can expect that by regulating the synaptic levels of glycine, GIyT-1 and GIyT-2 selectively modulate the activity of NMDA receptors and strychnine-sensitive glycine receptors, respectively.
Compounds that inhibit or activate glycine transporters would thus be expected to alter receptor function, and provide therapeutic benefits in a variety of disease states. Thus, inhibition of GIyT-2 could be used to diminish the activity of neurons having strychnine-sensitive glycine receptors via increasing synaptic levels of glycine, and so diminish the transmission of pain-related (i.e., nociceptive) information in the spinal cord, which has been shown to be mediated by these receptors. Yaksh, Pain, 37, 111-123 (1989). Additionally, enhancing inhibitory glycinergic transmission through strychnine-sensitive glycine receptors in the spinal cord can be used to decrease muscle hyperactivity, which is useful in treating diseases or conditions associated with increased muscle contraction, such as spasticity, myacIonus, and epilepsy {Truong et al., Movement Disorders, 3 , 77-87 (1988); Becker, I~ASEB J, 4 2767-2774 (1990)).
Spasticity that can be treated via modulation of glycine receptors is associated with epilepsy, stroke, head trauma, multiple sclerosis, spinal cord injury, dystonia, and other conditions of illness and injury of the nervous system.
NMDA receptors are involved in memory and Teaming (Rison and Stanton, Neurosci.
Biobehav. Rev., 19, 533 552 (1995); Danysz at al., Behavioral Pharmacol , 6, (1995)); and decreased function of NMDA-mediated neurotransmission appears to contribute to the symptoms of schizophrenia (Olney and Farber, Archives General Psvchiatrv, 52, 998-1007 (1996). Thus, agents that inhibit GIyT-1 and thereby increase glycine activation of NMDA receptors can be used as novel antipsychotics and anti-dementia agents, and to treat other diseases in which cognitive processes are impaired, such as attention deficit disorders and organic brain syndromes.
Conversely, over-activation of NMDA receptors has been implicated in a number of disease states, in particular the neuronal death associated with stroke, head trauma and possibly neurodegenerative diseases, such as Alzheimer's disease, mufti-infarct dementia, AIDS
dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or other conditions in which neuronal cell death occurs. Coyle & Puttfarcken, Science, 262, 689-695 (1993); Lipton and- Rosenberg, New Engl. J. of Medicine, 330, 613-(1993); Choi, Neuron 1, 623-634 (1988). Thus, phamlacological agents that increase the activity of GIyT-1 will result in decreased glycine-activation of NMDA
receptors, which activity can be used to treat these and related disease states.
Similarly, drugs that directly block the glycine site on the NMDA receptors can be used to treat these and related disease states.
For administration purposes, the subject compounds may be formulated into various pharmaceutical compositions comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a novel compound of formula (I). To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, in addition salx or in free acid or base form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid earners such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid WO 99/~t5011 PCT/EP99/01308 pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable solutions containing compounds of formula (I) may be formulated in an oil for prolonged action.
Appropriate oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soy bean oil, synthetic glycerol esters of long chain fatty acids and mixtures of these and other oils. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment. Addition salts of (I) due to their increased water solubility over the corresponding free base or free acid form, are obviously more suitable in the preparation of aqueous compositions.
It is especially advantageous to formulate the aforementioned pharmaceutical composi-tions in dosage unit form for ease of administration and uniformity of dosage.
Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with the required pharmaceutical Garner. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
The following examples are intended to illustrate the present invention.
Exverimental part Example A.1 A mixture of dimethyl (tetrahydro-3,3-diphenyl-2-furylidene) ammonium bromide (0.01 mol), prepared as described in US 3,714,159, (~)-4-(11,12-dihydro-6H
benzimidazo[2,1-b][3]benzazepin-6-yl)-piperidine (0.01 mol), Na2CO3 (0.01 mol) and KI (10 mg) in methyl isobutyl keton (200mL) was stirred and refluxed overnight. The solvent was evaporated and the residue taken up in water/CH2Cl2. The organic layer was separated and the water layer was extracted again with CH2C12. The combined organic layers were dried, filtered and the solvent evaporated. The residue was purified on a glass filter over silica gel (eluent : CH2Cl2/CHaOH 95/S to 90/10). The pure fractions were collected and evaporated. The residue was crystallized from CH3CN, yielding 0.88g (15%) of (~)-4-(11,12-dihydro-6H-benzimidazo[2,1-b][3]benzazepin-6-yl)-N,N dimethyl-a,a-diphenyl-1-piperidinebutanamide (comp. I; mp. 255.3 °C).
Example A.2 To a stirred mixture of 4-(3-bromo-2-oxopropyl)-N,N-dimethyl-a,a-diphenyl-1-piperidinebutanamide monohydrobromide (13 g) in methanol (80 ml) was added (2,6-dimethylphenyl)thiourea (4.1 g) at 70 °C. Stirnng was continued for 1 hour at reflux temperature. The solvent was evaporated and the residue was taken up in water.
Potassium carbonate was added untill a pH of about 9 and the mixture was extracted with ethylacetate. The organic phase was purified by acid base extraction, dried, filtered and the solvent evaporated. The residue was crystallized from methanol. The precipitate was filtered off, washed and dried, yielding 6.7 g (52 %) of 4-[[2-[[2,6-dimethylphenyl)amino]-4-thiazolyl]methyl)-N,N-dimethyl-a,a-diphenyl-1-piperidine-butanamide (comp. 47; mp. 210.5 °C).
In an analogous way were prepared 4-[[2-[[2,6-dichlorophenyl)amino]-4-thiazolyl]methyl]-N,N-dimethyl-a,a-diphenyl-1-piperidinebutanamide (comp. 48; mp. 207.0 °C);
N,N-dimethyl-4-[[2-(methylamino)-4-thiazolyl]methyl]-a,a-diphenyl-1-piperidine-butanamide (comp. 49; mp. 188.3 °C).
Example A.3 To a stirred mixture of NaH (78 % dispersion; 0.55 g) in 1,4-dioxane (50 ml) was added 1-(4-fluorophenyl)-N,N dimethyl-4-oxo-a,a-Biphenyl-1,3,8-triazaspiro[4,5]-decane-8-butanamide (7.7 g). After stirring for 1 hour at room temperature, the mixture was heated to 60 °C and (chloromethyl)benzene (2.3 g) was added.
Stirnng was continued overnight at 60 °C. the reaction mixture was poured out onto water and the mixture was extracted with CHCl3. The extract was washed with water, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel using a mixture of CHC13 and 3 % methanol, saturated with gaseous ammonia, as eluent.The pure fractions were collected and the solvent evaporated. The residue was triturated in n-hexane. The precipitate was filtered off and dried, yielding 2 g of 1-(4-fluorophenyl)-N,N-dimethyl-4-oxo-a,a-Biphenyl-3-phenylmethyl-1,3,8-triazaspiro[4,5]decane-8-butanamide (comp. 50; mp. 139.8 °C).
Tables 1 and 2 list compounds which were prepared according to example A.1.
Some compounds were prepared using a different base and/or solvent as regards the ones used in example A.I. Also, some compounds were prepared without using KI. The reaction conditions are mentioned in column "reaction conditions" in tables 1 and 2. In said column, MIK means methylisobutyl keton, DMA means N,N dimethylacetamide and DMF means N,N-dimethylformamide.
Table 1 °' RS R4 Reaction conditions Physical properties base / KI I solvent meltin oint : m . in °C
N
1 ~ ~ N -' H Na2C03 I KI / MIK mp. 255.3°C
2 <'N~~ I ~ H Na2C03 / KI / DMA mp. 173.7°C
~N
Br N
3 ~ / N ~ ~ H Na2C0.3 / KI / MIK mp. 210.6°C
_.
H Na2C0~ I - I MIK
~N _ H Na2C03 / - / DMF mp. 239.0°C;
Ntt~ \ /
HZO (1:1); HCl (1:2) 6 ~ ~ H Et3N / - / DMF mp. 168.8°C; HBr ( 1:2) ~~s N
,7 N
H Na2C03 / - / MIK mp. 196.4°C
U
°' RS R' Reaction conditions Physical properties vo. base ! KI / solvent meltin oint : m . in °C
s ~ "~ ~ ~ ~=QH
N H NazC03 I - I MIK mp. 128.9°C; H20 (1:1) -NH--<
N
H
H NazC03 I KI I M1K mp. 184.5°C
N ~ OH
-CHZ
~N I ~
°
10 ~ Hz \ ~ H NazCO 3 / KI / MIK mp. 161.4°C
N
CH2~~
N
11 CH, ~ ~ F
OH NazCO3 I KI I MIK mp. 170.5°C
N
-CH2 \\
N /
12 -cHZ / \ cH3 OH NazC03 I KI I MIK mp. 135°C
13 / \ c~ o-~'~'x Et3N / - / DMA mp. 161.3°C;
o HCl ( 1:1 ); H20 ( 1:1 ) _ II
14 CH-C-CHz-CH3 H NazC03 / - / MIK mp. 160.7°C;
ethanedioate (3:2) 15 ~ ~ ~ H NazC03 / KI / MIK mp. 265.4°C; HBr(2:1) o H NazC03 I - I MIK mp. 139.1 °C
i Hy-CH3 17 -NH N \ H NazC03 I KI I MIK mp. 199.4°C
---y ''~l N /
O _ 18 -c-NH-cHZ ~ ~ -~ / ~ NazC03 I KI I MIK mp. 111.5-145°C;
_ H20 (2:1) ' ~ / NazCO~ I - I MIK mp. 188.8°C
- -I S-°' RS R' Reaction conditions Physical properties ~o. base l KI I solvent melon oint : m . in °C
20 -o-~-~H
Na2C03 / KI / MIK mp. 111.9°C ; HCl (2:1) II
H Na2C03 / - / MIK mp. 202-205°C
H
\ N
22 -NH~ ~>'-oF3 H Na2CO3 / KI / DMF mp. 192.4°C
N
\N~ N
23 / ~ H Na2CO 3 / KI / MIK mp. IS6.1°C
Ci 24 ~ I H I Na2CO3 I KI / MIK , mp. 208.9°C
(1:1) s \
25 '°HZ-~~N ~ , OH Na2C03 I - I MIK mp. 257.4°C
i o~ H NaZCO~ / - / MIK mp. 176.2°C;
E)-2-butenedioate (I:1) CH,_ 27 ~ N H NazC03 / - / MIK mp. 142.7°C
N ~ /
28 / \ H Na2C03 I - I MIK mp. 198.0°C;
ethanedioate (I:I) Cl I -O C
29 ~ H Na2C0~ / KI / MIK mp. 133.1-135.1 °C;
ethanedioate (2:S) S
30 -~Z~N ~ / H NaHC03 / - / DMF m . 14 ° .
p 8.7 C, s~ ethanedioate (1:2) ~~S-CH3 31 -~HZ ~ ~~N H NaHC03 / - I DMF mp. 121.8°C
' Rs R4 Reaction conditionsPhysical properties vo. base / KI / meltin oint :
c~ solvent m . in C
32 s H NaHC03 / - mp. 251.0C
/ DMF
cl 33 cHZ ~ / F OH Et3N / - / m . 1 DMF p 83.3 C
N /
~3 N~-r ~ / H NaHC03 / - mp. 257.3C
/ DMF
N
~3 35 i Z ~ / F H Et3N / - / m . 136.
DMF p S C, N \ ethanedioate {
'IH~ 1:3) OH N /
36 cHz ~
I H Na2C03 / - mp. 207.4C;
I DMF
N \ ethanedioate ( ~ 1:2) N
37 cHz ~ / F OCH3 Na2C03 / - m . 22 . .
I / DMF p 0 1 C, N ~ (E)-2-butenedioate {1:1) N /
CI
38 s ri,., ~ / OH NaHCO 3 / - mp. 183.7C;
/ DMF
N CI (2:1); ethanol (1:1) cl 39 s -N,j ~ / OH NaHC03 I - mp. 198.7C
I DMF
N
cx, S
~~
40 cH2 H Na2C03 / - p. 183.9C
m / DMA
N \
~~2 S
41 CHz I ~ ~
H NazC03 / - mp. 201.4C;
/ DMA
'CH N \ (E)-2-butenedioate (2:3) N /
' R5 R Reaction conditionsPhysical properties ~o. base / KI / meltin oint :
solvent m . in C
s 42 H Na2C03 / - mp. 177.8C;
cH, N ~ / DMF
(Z)-2-butenedioate (1:2) _ ~
43 ~ ~ ~ ~
H Na2CO3 / KI m .
/ DMF p 190.5 C
_ 53 i 2 ~ / F OH Na2C03 / - m . 164.
/ MIK p SC
N
-CHZ_NH
~
N
O
54 -~c-cH' CHZ-O-CH3Na2CO3 / - mp. 155.4C; HCI
/ MIK (1:1) Table 2 f/ ~ p /CH3 N
\CH3 \CH~-CHZ_N\~R3 o.
R3 Reaction conditionsPhysical properties vo. base / KI I melon oint : m solvent . in C
N
~ Na2C03 l KI m N p.
f .
;
r,... \ (E)-2-butenedioate ( 1:1 ) N
45 CN i Na2C03 / KI mp. 174.5C
-, \ / MIK
Also prepared according to example A.1 but without using KI was 1-(5-chloro-2-methyl-phenyl)-N,N-dimethyl-4-oxo-a,a-Biphenyl-1,3,8-triazaspiro[4,5]decane-8-butanamide (comp. 46; mp. 175.7°C).
Pharmacological example Example B.l: Assay of transport via GIyTI transnorters Subconfluent HEK 293 -GIyTl cells (i.e. a cell line which stably expresses human glycine transporter 1) were seeded in Cytostar-T plates at a concentration of 50,000 cells per well in 100 pl DMEM medium (Dulbecco's Modified Eagle Medium supplemented with 10% foetal bovine serum, 1 mM Na-pyruvate, 2 mM glutamine, WO 99/45011 PC"T/EP99/01308 U penicillin/ml and 0.1 mg/ml streptomycin). The cells were incubated for 48 hours at 37°C, 5% C02, 95% humidity.
On day 3, the cells were washed using a Tecan PW96 microprocessor controlled washer S designed to wash all 96 wells of a microplate simultaneously with uptake buffer (25 mM Hepes, 5.4 mM K-gluconate, 1.8 mM Ca-gluconate, 0.8 mM MgS04, 140 mM
NaCI, S mM glucose, 5 mM alanine, adjusted to pH 7.5 with 2M Tris). The Tecan PW96 was programmed to wash the cells five times leaving 75 pI in each well.
The test compounds were dissolved at different concentrations in the micromolar range in DMSO. 1 lrl Test solution was added to each well and the cells were incubated for 5' to 10' at ambient temperature. Then there was added 25 ~tl 30 ~.M
[U'4C]glycine diluted in uptake buffer. The cells were incubated for 1 hour at ambient temperature.
The plates were then sealed and [U'4C]glycine uptake was determined on a Packard microplate scintillation counter (TopCount). From the results obtained for the various concentrations of each test drug, the concentration giving 50 % inhibition {ICso) of glycine uptake was calculated. Calculated data for the test compounds according to the instant invention are shown in table 3 as pICso values (negative log values of the ICso).
Compound 51 being 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-N,N-dimethyl-a,a-diphenyl-1-piperidinebutanamide as disclosed in US-4,695,575 and compound 52 being 4-[[9-[(4-methoxyphenyl)methyl]-9H-purin-8-yl]amino]-N,N-dimethyl-a,a-diphenyl-1-piperidinebutanamide {E)-2-butenedioate (2:5) as disclosed in US-5,008,268 were also tested.
Table 3 Comp. PICso Comp. PICso No. No.
1 7.28 28 6.56 2 6.80 29 6.10 3 6.77 30 6.63 4 6.49 31 6.17 6.43 32 6.12 6 6~1~ 33 6.21 7 6.16 34 6.35 8 6.05 35 7.22 9 6.13 36 6.25 10 6.62 37 6.90 11 6.89 38 6.04 12 6.15 39 6.23 Comp. PICso Comp. PICso No. No.
13 6.28 40 6.36 14 6.03 41 6.52 15 6.04 42 6.12 16 6.12 43 6.12 I7 6.13 44 6,70 18 6.03 45 6.00 19 6.29 46 6.27 20 6.39 47 6.79 21 6.08 48 6.54 22 6.03 49 6.12 23 6.03 50 6.60 24 6.08 51 6.91 25 6.36 52 6.47 26 6.10 53 6.39 27 6.26 54 6.61 C.
Composition examples The following formulation exemplifies a typical pharmaceutical composition suitable for animal systemic and administration hu to b man su jects in accordance with the present invention. "Active ingredient" (A.L) relates to a compound of formula {I) or a pharmaceutically acceptable addition salt thereof.
Example C.1 ~ film-coated tablets Preparation of tablet core.A mixture of 100 of the A.L, 570 g lactose and 200 g starch was mixed well and thereafter humidified with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone in about 200 ml of water. The wet powder mixture was sieved, dried and sieved again. Then there was added 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. The whole was mixed well and compressed into tablets, giving 10.000 tablets, each comprising 10 mg of the active ingredient.
Coating To a solution of 10 g methyl cellulose in 75 m1 of denaturated ethanol there was added a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane.
Then there were added 75 mI of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of polyethylene glycol was molten and dissolved in 75 mI of dichloromethane. The latter solution was added to the former and then there were added 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of concentrated color suspension and the whole was homogenated. The tablet cores were coated with the thus obtained mixture in a coating apparatus.
Composition examples The following formulation exemplifies a typical pharmaceutical composition suitable for animal systemic and administration hu to b man su jects in accordance with the present invention. "Active ingredient" (A.L) relates to a compound of formula {I) or a pharmaceutically acceptable addition salt thereof.
Example C.1 ~ film-coated tablets Preparation of tablet core.A mixture of 100 of the A.L, 570 g lactose and 200 g starch was mixed well and thereafter humidified with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone in about 200 ml of water. The wet powder mixture was sieved, dried and sieved again. Then there was added 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. The whole was mixed well and compressed into tablets, giving 10.000 tablets, each comprising 10 mg of the active ingredient.
Coating To a solution of 10 g methyl cellulose in 75 m1 of denaturated ethanol there was added a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane.
Then there were added 75 mI of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of polyethylene glycol was molten and dissolved in 75 mI of dichloromethane. The latter solution was added to the former and then there were added 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of concentrated color suspension and the whole was homogenated. The tablet cores were coated with the thus obtained mixture in a coating apparatus.
Claims (10)
1. The use of a glycine transport inhibiting compound for the preparation of a medicament for treating disorders of the central and peripheral nervous system, said compound having the formula a N-oxide, a stereochemically isomeric form or a pharmaceutically acceptable addition salt thereof, wherein R1 and R2 each independently represent hydrogen or C1-4alkyl;
X represents a radical of formula wherein the dotted line represents an optional bond;
~R3 represents a radical of formula wherein R6 and R7 each represent hydrogen or both may be taken together with the two carbon atoms to which they are attached to form a phenyl ring;
R8 represents hydrogen or halo;
n is 1 or 2;
R4 represents hydrogen, hydroxy, C1-4alkyloxy, C1-4alkyloxyC1-4alkyl, or arylC1-4alkyloxy;
R5 represents diarylmethyloxyC1-4alkyl or a radical of formula wherein B1 represents -CH2, -CH(OH)-, -NH- , -CH2-NH- or a direct bond;
B2 represents -NH-, -CH2- or a direct bond;
B3 represents -NR12-, -CH2-, -C(=O)- or a direct bond;
B7 represents -C1-4alkanediyl-NH- or -NH-C1-4alkyl-;
B8 represents -NR19-, -CH2- or -CH(aryl)-;
each Y independently represents O or S;
-a1=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH- (b-1-a) or -N=CH-N=CH- (b-1-b);
wherein a hydrogen atom in radical (b-1-a) may be replaced by hydroxy;
R9 represents C1-4alkyl; or C1-alkyl substituted with aryl, thienyl, furanyl, furanyl substituted with hydroxyC1-4alkyl, or thiazolyl;
R10 represents aryl, arylamino, C1-4alkylamino, C1-4alkylthio;
R11 represents hydrogen, C1-4alkyl, halo or trifluoromethyl;
R12 represents hydrogen or C1-4alkylcarbonyl;
R13 represents hydrogen, C1-4alkyl or aryl;
R14 represents hydrogen or halo;
R15 and R16 each independently represent hydrogen or aryl;
R17 represents hydrogen or C1-4alkyl;
R18 represents aryl, 10,11-dihydro-5H-dibenz[b,f]azepin-5-yl or C1-4alkyl optionally substituted with one or two substituents each independently selected from C3-7cycloalkyl and aryl;
R19 represents hydrogen, C1-4alkylcarbonyl or diarylC1-4alkyl;
R20, R21, R22 and R23 each independently represent hydrogen, C1-4alkyl or aryl;
R24 represents hydrogen or trifluoromethyl;
R25 represents hydrogen or halo; and in case R5 represents a radical of formula (b-3), then R4 may also be phenylC1-4alkylaminocarbonyl; and R4 and R5 may be taken together to form a spiro radical of formula wherein R26 and R27 each independently represent hydrogen, C1-4alkyl, aryl or arylC1-4alkyl;
aryl represents phenyl, or phenyl substituted with 1 or 2 substituents independently selected from C1-4alkyl, halo, trifluoromethyl, hydroxy and C1-4alkyloxy.
X represents a radical of formula wherein the dotted line represents an optional bond;
~R3 represents a radical of formula wherein R6 and R7 each represent hydrogen or both may be taken together with the two carbon atoms to which they are attached to form a phenyl ring;
R8 represents hydrogen or halo;
n is 1 or 2;
R4 represents hydrogen, hydroxy, C1-4alkyloxy, C1-4alkyloxyC1-4alkyl, or arylC1-4alkyloxy;
R5 represents diarylmethyloxyC1-4alkyl or a radical of formula wherein B1 represents -CH2, -CH(OH)-, -NH- , -CH2-NH- or a direct bond;
B2 represents -NH-, -CH2- or a direct bond;
B3 represents -NR12-, -CH2-, -C(=O)- or a direct bond;
B7 represents -C1-4alkanediyl-NH- or -NH-C1-4alkyl-;
B8 represents -NR19-, -CH2- or -CH(aryl)-;
each Y independently represents O or S;
-a1=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH- (b-1-a) or -N=CH-N=CH- (b-1-b);
wherein a hydrogen atom in radical (b-1-a) may be replaced by hydroxy;
R9 represents C1-4alkyl; or C1-alkyl substituted with aryl, thienyl, furanyl, furanyl substituted with hydroxyC1-4alkyl, or thiazolyl;
R10 represents aryl, arylamino, C1-4alkylamino, C1-4alkylthio;
R11 represents hydrogen, C1-4alkyl, halo or trifluoromethyl;
R12 represents hydrogen or C1-4alkylcarbonyl;
R13 represents hydrogen, C1-4alkyl or aryl;
R14 represents hydrogen or halo;
R15 and R16 each independently represent hydrogen or aryl;
R17 represents hydrogen or C1-4alkyl;
R18 represents aryl, 10,11-dihydro-5H-dibenz[b,f]azepin-5-yl or C1-4alkyl optionally substituted with one or two substituents each independently selected from C3-7cycloalkyl and aryl;
R19 represents hydrogen, C1-4alkylcarbonyl or diarylC1-4alkyl;
R20, R21, R22 and R23 each independently represent hydrogen, C1-4alkyl or aryl;
R24 represents hydrogen or trifluoromethyl;
R25 represents hydrogen or halo; and in case R5 represents a radical of formula (b-3), then R4 may also be phenylC1-4alkylaminocarbonyl; and R4 and R5 may be taken together to form a spiro radical of formula wherein R26 and R27 each independently represent hydrogen, C1-4alkyl, aryl or arylC1-4alkyl;
aryl represents phenyl, or phenyl substituted with 1 or 2 substituents independently selected from C1-4alkyl, halo, trifluoromethyl, hydroxy and C1-4alkyloxy.
2. The use according to claim 1 wherein R1 and R2 are methyl.
3. The use according to claim 1 or 2 wherein X is a radical of formula (a) or (b).
4. The use according to claim 1 wherein the disorder is psychoses, pain, epilepsy, a neurodegenerative diseases, stroke, head trauma or multiple sclerosis.
5. A compound of formula (I) as defined in any one of claims 1 to 3 provided that when R4 is hydrogen and R5 is a radical of formula (b-1) wherein B1 is -CH2- and R9 is 4-fluorobenzyl, then -a1=a2-a3=a4- is other than -CH=CH-CH=CH-; and when R4 is hydrogen and R5 is a radical of formula (b-1) wherein B1 is -NH- and R9 is 4-methoxybenzyl, then -a1=a2-a3=a4- is other than -CH=N-CH=N-.
6. A compound as claimed in claim 5 wherein R5 is diarylmethyloxyC1-4alkyl or a radical of formula (b-2), (b-3), (b-4), (b-5), (b-6), (b-7), (b-8), (b-9), (b-10), (b-11), (b-12) or (b-13); or R5 may be taken together with R4 to form a spiro radical of formula (b-14).
7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound as described in claims 5 or 6.
8. A process of preparing a pharmaceutical composition as claimed in claim 7, characterized in that, a therapeutically effective amount of a compound as claimed in claims 5 or 6 is intimately mixed with a pharmaceutical carrier.
9. A compound as described in claims 5 or 6 for use as a medicine.
10. A process of preparing a compound as described in claim 5, characterized by, reacting an intermediate of formula (II) wherein W is an appropriate counter ion or a functional derivative thereof with an intermediate of formula (III) in a reaction-inert solvent, in the presence of a suitable base and optionally in the presence of potassium iodide;
and, if desired, converting the compounds of formula (I), into an acid addition salt by treatment with an acid, or into a base addition salt by treatment with a base, or conversely, converting the acid addition salt form into the free base by treatment with alkali, or converting the base addition salt into the free acid by treatment with acid; and, if desired, preparing N oxide and/or stereochemically isomeric forms thereof.
and, if desired, converting the compounds of formula (I), into an acid addition salt by treatment with an acid, or into a base addition salt by treatment with a base, or conversely, converting the acid addition salt form into the free base by treatment with alkali, or converting the base addition salt into the free acid by treatment with acid; and, if desired, preparing N oxide and/or stereochemically isomeric forms thereof.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP98200700.7 | 1998-03-06 | ||
| EP98200700 | 1998-03-06 | ||
| PCT/EP1999/001308 WO1999045011A1 (en) | 1998-03-06 | 1999-02-26 | Glycine transport inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2322136A1 true CA2322136A1 (en) | 1999-09-10 |
Family
ID=8233443
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002322136A Abandoned CA2322136A1 (en) | 1998-03-06 | 1999-02-26 | Glycine transport inhibitors |
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| Country | Link |
|---|---|
| EP (1) | EP1058684A1 (en) |
| JP (1) | JP2002505332A (en) |
| KR (1) | KR20010032967A (en) |
| CN (1) | CN1291984A (en) |
| AU (1) | AU3254499A (en) |
| BG (1) | BG104686A (en) |
| BR (1) | BR9907953A (en) |
| CA (1) | CA2322136A1 (en) |
| EE (1) | EE200000483A (en) |
| HR (1) | HRP20000524A2 (en) |
| HU (1) | HUP0101281A3 (en) |
| IL (1) | IL138227A0 (en) |
| NO (1) | NO20004432L (en) |
| PL (1) | PL342818A1 (en) |
| SK (1) | SK13092000A3 (en) |
| TR (1) | TR200002570T2 (en) |
| WO (1) | WO1999045011A1 (en) |
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|---|---|---|---|---|
| UA73749C2 (en) * | 1999-11-01 | 2005-09-15 | Diarylenines | |
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| FR2842804B1 (en) | 2002-07-29 | 2004-09-03 | Sanofi Synthelabo | N- [PHENYL (PIPERIDIN-2-YL) METHYL] BENZAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
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| BRPI0413497B8 (en) * | 2003-08-11 | 2021-05-25 | Hoffmann La Roche | piperazine with or substituting phenyl group, and its use and preparation process, as well as medicine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3714159A (en) * | 1971-03-30 | 1973-01-30 | Janssen Pharmaceutica Nv | 2,2-diaryl-4-(4'-aryl-4'-hydroxy-piper-idino)-butyramides |
| US4695575A (en) * | 1984-11-13 | 1987-09-22 | Janssen Pharmaceutica, N.V. | 4-[(bicycle heterocyclyl)-methyl and -hetero]-piperidines |
| GB8515934D0 (en) * | 1985-06-24 | 1985-07-24 | Janssen Pharmaceutica Nv | (4-piperidinomethyl and-hetero)purines |
| CA1332236C (en) * | 1985-10-11 | 1994-10-04 | Lourens Wals | ,--diaryl-4-aryl-4-hydroxy-1-piperidinebutanamide, n-oxides |
| CA2255727A1 (en) * | 1996-05-31 | 1997-12-04 | Trophix Pharmaceuticals, Inc. | Pharmaceutical for treating of neurological and neuropsychiatric disorders |
-
1999
- 1999-02-26 SK SK1309-2000A patent/SK13092000A3/en unknown
- 1999-02-26 TR TR2000/02570T patent/TR200002570T2/en unknown
- 1999-02-26 BR BR9907953-4A patent/BR9907953A/en not_active Application Discontinuation
- 1999-02-26 CN CN99803530A patent/CN1291984A/en active Pending
- 1999-02-26 HU HU0101281A patent/HUP0101281A3/en unknown
- 1999-02-26 EE EEP200000483A patent/EE200000483A/en unknown
- 1999-02-26 AU AU32544/99A patent/AU3254499A/en not_active Abandoned
- 1999-02-26 KR KR1020007006314A patent/KR20010032967A/en not_active Application Discontinuation
- 1999-02-26 EP EP99937930A patent/EP1058684A1/en not_active Withdrawn
- 1999-02-26 WO PCT/EP1999/001308 patent/WO1999045011A1/en not_active Application Discontinuation
- 1999-02-26 CA CA002322136A patent/CA2322136A1/en not_active Abandoned
- 1999-02-26 IL IL138227??A patent/IL138227A0/en unknown
- 1999-02-26 JP JP2000534553A patent/JP2002505332A/en not_active Withdrawn
- 1999-02-26 PL PL99342818A patent/PL342818A1/en unknown
-
2000
- 2000-08-02 HR HR20000524A patent/HRP20000524A2/en not_active Application Discontinuation
- 2000-08-11 BG BG104686A patent/BG104686A/en unknown
- 2000-09-05 NO NO20004432A patent/NO20004432L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| PL342818A1 (en) | 2001-07-02 |
| TR200002570T2 (en) | 2000-12-21 |
| JP2002505332A (en) | 2002-02-19 |
| HUP0101281A2 (en) | 2001-09-28 |
| NO20004432D0 (en) | 2000-09-05 |
| SK13092000A3 (en) | 2001-03-12 |
| EP1058684A1 (en) | 2000-12-13 |
| WO1999045011A8 (en) | 1999-10-14 |
| BR9907953A (en) | 2000-10-24 |
| WO1999045011A1 (en) | 1999-09-10 |
| BG104686A (en) | 2001-04-30 |
| IL138227A0 (en) | 2001-10-31 |
| AU3254499A (en) | 1999-09-20 |
| CN1291984A (en) | 2001-04-18 |
| KR20010032967A (en) | 2001-04-25 |
| HUP0101281A3 (en) | 2001-11-28 |
| HRP20000524A2 (en) | 2001-02-28 |
| NO20004432L (en) | 2000-11-02 |
| EE200000483A (en) | 2002-02-15 |
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