US20020147359A1 - Intermediate compound for preparing guanidine and amidine derivatives - Google Patents
Intermediate compound for preparing guanidine and amidine derivatives Download PDFInfo
- Publication number
- US20020147359A1 US20020147359A1 US10/085,818 US8581802A US2002147359A1 US 20020147359 A1 US20020147359 A1 US 20020147359A1 US 8581802 A US8581802 A US 8581802A US 2002147359 A1 US2002147359 A1 US 2002147359A1
- Authority
- US
- United States
- Prior art keywords
- compounds
- phenyl
- alkyl
- denotes
- methyl
- 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
Links
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D233/44—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
- C07D239/12—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Definitions
- the invention relates to new guanidine and amidine derivatives of general formula I
- the compounds are valuable neurokinin (tachykinin) antagonists.
- FAB-MS fast atom bombardment mass spectroscopy
- TBTU O-benzotriazolyl-tetramethyluronium tetrafluoroborate
- the invention relates to new guanidine and amidine derivatives of general formula I
- X denotes N—R 3 or CH—R 4 , wherein R 3 denotes
- R 5 , R 6 and R 7 independently of one another denote H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, alkanoyl, benzoyl, heteroaryl, dialkylamino, dialkylaminoalkyl, trialkylammoniumalkyl, cyano, alkyloxycarbonyl, aralkyloxycarbonyl, OH, O-alkyl or O-aryl, wherein the alkyl groups contain 1 to 5 carbon atoms, the cycloalkyl groups contain 3 to 6 carbon atoms, the alkenyl groups contain 2 to 5 carbon atoms, aryl denotes phenyl, or phenyl or naphthyl substituted by methyl or halogen (F, Cl, Br, I); or R 5 and R 6 or R 6 and R 7 together form the group (CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 )
- R 8 H, alkyl with 1 to 5 carbon atoms or cycloalkyl with 3 to 6 carbon atoms or R 7 +R 8 together form the group —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —(CH 2 ) 5 — or —(CH 2 ) 2 O(CH 2 ) 2 —; or R 4 denotes
- R 5 is as hereinbefore defined
- y denotes CH 2 or (CH 2 ) 2 ;
- z denotes O or H 2 ;
- Ar denotes unsubstituted or mono- to 5-substituted phenyl, or unsubstituted or mono- or disubstituted naphthyl [wherein the substituents of the phenyl and naphthyl independently of one another denote halogen (F, Cl, Br, I), OH, (C 1 - 4 )alkyl, O—(C 1 - 4 )alkyl, CF 3 , OCF 3 or NR 9 R 10 (wherein R 9 and R 10 independently of one another denote H, methyl or acetyl)] or Ar is phenyl substituted by —OCH 2 O— or —O(CH 2 ) 2 O—;
- R 1 denotes phenyl (C 1 - 4 )alkyl or phenyl(C 1 - 4 )alkanoyl or naphthyl(C 1 - 4 )alkyl or naphthylacetyl, wherein phenyl may be substituted by 1 to 3 substituents, wherein the substituents independently of one another denote halogen (F, Cl, Br, I), (C 1 - 4 )alkyl, O—(C 1 - 4 )alkyl, CF 3 , OCF 3 or NR 19 R 20 (wherein R 19 and R 20 independently of one another denote H, methyl or acetyl); and
- R 2 denotes H, (C 1 - 4 )alkyl, (C 3 - 6 )cycloalkyl, CH 2 COOH, —CH 2 C(O)NH 2 , OH or phenyl(C 1 - 4 )alkyl.
- the compounds according to the invention are valuable neurokinin (tachykinin) antagonists which have both substance P antagonism and also neurokinin-A- or neurokinin-B-antagonistic properties. They are useful for the treatment and prevention of neurokinin-mediated diseases.
- tachykinin tachykinin
- Compounds of general formula I may contain acid groups, mainly carboxyl groups, and/or basic groups such as amino functions, for example.
- Compounds of general formula I may therefore occur as internal salts, salts with pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, sulphonic acid or organic acids (such as, for example, maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically acceptable bases such as alkali metal or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as e.g. diethylamine, triethylamine, triethanolamine, etc.
- the compounds according to the invention may occur as racemates, but may also be obtained as pure enantiomers, i.e. in the (R) or (S) form. Compounds which occur as racemates or in the (S) form are preferred.
- the receptor affinity for the NK 1 receptor (substance P receptor) is determined on human lymphoblastoma cells (IM-9) with cloned NK 1 receptors, by measuring the displacement of 125 I-labelled substance P.
- the K i values thus obtained show the efficacy of the compounds.
- Example no. K i [nMol/L] 1 0.45 2 0.30 3 0.20 4 0.53 5 6.28 6 0.88 7 1.45 8 0.19 9 0.14 10 0.12 12 0.32 27 1.11 28 4.16 29 0.87 30 0.17 31 8.96 32 0.20 33 13.25 34 0.37 35 0.78
- the compounds according to the invention are valuable neurokinin (tachykinin) antagonists which have both substance P antagonism and also neurokinin-A- or neurokinin-B-antagonistic properties. They are useful for the treatment and prevention of neurokinin-mediated diseases:
- the respiratory tract such as asthma, chronic bronchitis, hyperreactive respiratory tract, emphysema, rhinitis, cough,
- gastro-intestinal tract such as gastric and duodenal ulcers, ulcerative colitis, Crohn's disease, irritable bowel, Hirschsprung's disease,
- Alzheimer's disease for treating diseases of the central nervous system, such as dementia, Alzheimer's disease, schizophrenia, psychoses, depression, headache (e.g. migraine or tension headaches), epilepsy; Parkinson's disease, stroke,
- diseases of the central nervous system such as dementia, Alzheimer's disease, schizophrenia, psychoses, depression, headache (e.g. migraine or tension headaches), epilepsy; Parkinson's disease, stroke,
- the invention therefore also relates to the use of the compounds according to the invention as curative agents and pharmaceutical preparations which contain these compounds. They are preferably used in humans.
- the compounds according to the invention may be administered by intravenous, subcutaneous, intramuscular, intraperitoneal or intranasal route, by inhalation, by transdermal route, if desired with the aid of iontophoresis or enhancers known from the literature, and by oral route.
- the compounds of formula I or the physiologically acceptable salts thereof are brought into solution, suspension or emulsion, optionally with the substances conventionally used for this, such as solubilisers, emulsifiers or other adjuvants.
- suitable solvents include, for example: water, physiological saline solutions or alcohols, e.g. ethanol, propandiol or glycerol, sugar solutions such as glucose or mannitol solutions or a mixture of different solvents.
- the compounds may be administered by means of implants, e.g. of polylactide, polyglycolide or polyhydroxybutyric acid or intranasal preparations.
- Preferred compounds of general formula 1 are those wherein
- X denotes N—R 3 or CH—R 4 , wherein
- R 3 denotes
- R 5 , R 6 and R 7 independently of one another denote H, alkyl, cycloalkyl, aryl, aralkyl, alkanoyl, benzoyl, dialkylamino, dialkylaminoalkyl, trialkylammoniumalkyl, cyano, alkyloxycarbonyl, aralkyloxycarbonyl, OH, O-alkyl or O-aryl,
- alkyl groups contain 1 to 4 carbon atoms
- the cycloalkyl groups contain 3 to 6 carbon atoms
- aryl denotes phenyl or phenyl substituted by methyl or halogen (F, Cl, Br, I);
- R 5 and R 6 or R 6 and R 7 together form the group —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —(CH 2 ) 5 —or —(CH 2 ) 2 O(CH 2 ) 2 ;
- R 8 H, alkyl with 1 to 5 carbon atoms or cycloalkyl with 3 to 6 carbon atoms or
- R 7 +R 8 together form the group —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —(CH 2 ) 5 — or —(CH 2 ) 2 O (CH 2 ) 2 —;
- Y denotes CH 2 or (CH 2 ) 2 ;
- Z denotes O or H 2 ;
- Ar denotes unsubstituted or mono- to 5-substituted phenyl [wherein the substituents of the phenyl independently of one another denote halogen (F, Cl, Br, I), OH, (C 1 -C)alkyl, O—(C 1 - 4 )alkyl, CF 3, OCF 3 or NR 9 R 10 (wherein R 9 and R 10 independently of one another denote H, methyl or acetyl)] or Ar is phenyl substituted by —OCH 2 O— or —O(CH 2 ) 2 O—;
- R 1 denotes phenyl(C 1 -C 4 )alkyl or phenyl(C 1 -C 4 )alkanoyl, wherein phenyl may be substituted by 1 to 3 substituents, wherein the substituents independently of one another denote halogen (F, Cl, Br, I), (C 1 - 4 )alkyl, O—(C 1 - 4 )alkyl, CF 3 , OCF 3 or NR 19 R 20 (wherein R 19 and R 20 independently of one another denote H, methyl or acetyl); and
- R 2 denotes H, (C 1 - 4 )alkyl or (C 3 - 6 )cycloalkyl.
- X denotes N-R 3 or CH-R 4 , wherein
- R 5 to R 8 , Z, Ar, R 1 and R 2 are as hereinbefore defined, and Y denotes CH 2 .
- Ar is unsubstituted phenyl, particularly those wherein
- Ar is phenyl mono- or disubstituted by halogen, preferably
- Ar is dichlorophenyl; and/or wherein R 1 denotes substituted phenylacetyl (preferably 3, 4-di-trifluoromethylphenyl-acetyl) or wherein R 1 is substituted phenylethyl, wherein the phenyl is substituted by 2 substituents which, independently of one another, denote halogen (F, Cl, Br, I), (C 1 - 4 )alkyl or CF 3 , particularly wherein the substituents of the phenyl are CF 3 , CH 3 or F, (preferably wherein the two substituents of the phenyl are CF 3 ); and/or wherein R 2 is (C 1 - 4 )alkyl, preferably wherein R 2 is methyl.
- R 1 denotes substituted phenylacetyl (preferably 3, 4-di-trifluoromethylphenyl-acetyl) or wherein R 1 is substituted phenylethyl, wherein the phenyl is
- One aspect of the invention relates to compounds of formula I wherein X denotes the group CR 4 , wherein
- R 4 is
- R 5 , R 6 , R 7 and R 8 independently of one another denote H, alkyl with 1 to 4 carbon atoms or cycloalkyl with 3 to 6 carbon atoms; or
- R 7 and R 8 together form the group (CH 2 ) 2 , (CH 2 ) 3 , (CH 2 ) 4 or (CH 2 ) 5 .
- Compounds wherein R 5 and R 6 denote H and R 7 and R 8 together form the group (CH 2 ) 2 or those wherein R 5 and R 6 denote H and R 7 and R 8 are cyclohexyl are preferred.
- Another important aspect of the invention relates to compounds of formula I wherein X is the group NR 3 wherein
- R 3 is
- R 5 and R 6 independently of one another denote H, alkyl with 1 to 4 carbon atoms, cycloalkyl with 3 to 6 carbon atoms, phenyl, or phenyl, benzyl or benzoyl substituted by methyl or halogen (F, Cl, Br, I), CN, alkyloxycarbonyl (wherein the alkyl group contains 1 to 4 carbon atoms), benzyloxycarbonyl, alkoxy with 1 to 4 carbon atoms or dialkylamine (wherein the alkyl groups contain 1 to 4 carbon atoms), R 7 denotes H or alkyl with 1 to 4 carbon atoms;
- R 5 and R 6 or R 6 and R 7 together form the group (CH 2 ) 2 , (CH 2 ) 3 , (CH 2 ) 4 or (CH 2 ) 5 ; or R 6 and R 7 together form the group —(CH) 2 —O—(CH 2 ) 2 —.
- R 5 and R 6 independently of one another denote H, alkyl with 1 to 4 carbon atoms, cycloalkyl with 3 to 6 carbon atoms, phenyl, phenyl, benzyl or benzoyl substituted by methyl or halogen (F, Cl, Br, I);
- R 7 is H or alkyl with 1 to 4 carbon atoms or R 5 and R 6 or R 6 and R7 together form the group (CH 2 ) 2 , (CH 2 ) 3 , (CH 2 ) 4 or (CH 2 ) 5 ; or R 6 and R 7 together form the group —(CH 2 ) 2 —O—(CH 2 ) 2 —;
- R 5 and R 6 independently of one another denote H, alkyl with 1 to 4 carbon atoms, cyclohexyl, phenyl, methyl-substituted phenyl, benzyl or benzoyl;
- R 7 is H or methyl
- R 5 and R 6 together form the group (CH 2 ) 2 or R 6 and R 7 together form the group (CH 2 ) 5 or —(CH) 2 —O—(CH 2 ) 2 —;
- R 5 denotes H, alkyl with 1 to 4 carbon atoms, cyclohexyl, methyl-substituted phenyl, benzyl or benzoyl;
- R 6 denotes H, alkyl with 1 to 3 carbon atoms, cyclohexyl, phenyl, methyl-substituted phenyl or benzyl;
- R 7 is H or methyl
- R 5 and R 6 together form the group —(CH 2 ) 2 —or R 6 and R 7 together form the group (CH 2 ) 2 —O—(CH 2 ) 2 —;
- R 5 and R 6 independently of one another denote H, CH 3 , CH(CH 3 ) 2 , phenyl or benzyl, R 7 is H or CH 3 , or
- R 5 and R 6 together form the group —CH 2 CH 2 —or R 6 and R 7 together form the group —(CH 2 ) 2 —O—(CH 2 ) 2 —.
- the compounds may be prepared by methods known per se. Advantageous methods are shown and described in the diagrams which follow.
- X denotes N-R 3 , wherein R 3 is
- [0094] may be prepared by reacting a compound of general formula I wherein R 3 denotes hydrogen with the corresponding amino-iminomethanesulphonic acid, the corresponding carbodiimide or thiourea.
- R 3 denotes hydrogen
- This process is illustrated by methods A to C for compounds wherein Y is CH 2 , Ar is phenyl, Z is oxo, R 1 is difluorophenylethyl and R 2 is methyl.
- the process can be used analogously for all compounds of formula I wherein X is NR 3 .
- Piperazine having a protecting group in the 1 position is reacted with 2-halophenyl-acetate to obtain N-protected piperazinyl-phenylacetate.
- This is saponified under suitable conditions, e.g. with sodium hydroxide solution, to obtain the corresponding carboxylic acid.
- This is then linked to an amine according to the invention, e.g. N-methyl-3,5-bis-trifluoromethylphenethyl-amine, using a suitable coupling reagent such as TBTU.
- the protecting group is cleaved from the piperazine part of the molecule using a suitable cleaving reagent.
- the free piperazine-N is reacted with unsubstituted or substituted amino-iminomethanesulphonic acid (which is obtained for example by oxidation of the corresponding thiourea using H 2 O 2 ) to obtain the desired guanidine.
- the compounds of the type in Examples 4 to 7 may advantageously be prepared according to method B, for example.
- Compounds of the type in Example 9 may advantageously be prepared according to method C, for example.
- [0107] may also be prepared by reacting the corresponding piperazine derivative or piperidine derivative with the coresponding amide.
- This process is illutrated by method D and analogous method E for compounds wherein Y denotes CH 2 , Ar is phenyl, Z is oxo, R 1 is difluorophenylethyl and R 2 is methyl.
- the process may be used analogously, however, for all compounds of formula I wherein X is NR 3 or CR 4 .
- Particularly prefered are compounds wherein
- reaction is carried out in an inert solvent in the presence of a base.
- the amide thus obtained is reacted with the piperazine derivative described above, whereupon a C—N bond is formed, with elimination of methanesulphonate, whilst at the same time the chiral centre is reversed.
- the reaction is carried out in an inert solvent such as e.g. DMF or acetonitrile in the presence of a base such as TEA or N-methylmorpholine, for example, at temperatures between 20° C. and 120° C.
- the reaction time is between 0.5 h and 48 h.
- (+)-enantiomer melting point 171-181 ° C.
- (+)-enantiomer FAB-MS: (M+H) + 584.
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Abstract
or the pharmaceutically acceptable salts thereof, wherein
X=N−R3 or CH−R 4,
Y=CH2 or (CH2)2,
Z=O or H2;
and R1, R2, R3, R4 and Ar have the meanings given in the specification, and the preparation and use thereof. The new compounds are valuable neurokinin (tachykinin) antagonists.
Description
- This application is a divisional of U.S. Ser. No.09/897,664 which is a divisional of U.S. Pat. No. 6,103,719.
-
- and the pharmaceutically acceptable salts thereof, processes for preparing them and pharmaceutical compositions containing these compounds. The compounds are valuable neurokinin (tachykinin) antagonists.
- The abbreviations used in this specification and claims are explained as follows:
- Boc=t-butyloxycarbonyl
- DC=thin layer chromatogram
- DMF=dimethylformamide
- EE=ethyl acetate
- FAB-MS=fast atom bombardment mass spectroscopy
- RT=room temperature
- TBTU=O-benzotriazolyl-tetramethyluronium tetrafluoroborate
- TEA=triethylamine
- THF=tetrahydrofuran
-
-
- or the pharmaceutically acceptable salts thereof, wherein
-
-
-
- wherein R5 is as hereinbefore defined;
- y denotes CH2 or (CH2)2;
- z denotes O or H2;
- Ar denotes unsubstituted or mono- to 5-substituted phenyl, or unsubstituted or mono- or disubstituted naphthyl [wherein the substituents of the phenyl and naphthyl independently of one another denote halogen (F, Cl, Br, I), OH, (C1-4)alkyl, O—(C1-4)alkyl, CF3, OCF3 or NR9R10 (wherein R9 and R10 independently of one another denote H, methyl or acetyl)] or Ar is phenyl substituted by —OCH2O— or —O(CH2)2O—;
- R1 denotes phenyl (C1-4)alkyl or phenyl(C1-4)alkanoyl or naphthyl(C1-4)alkyl or naphthylacetyl, wherein phenyl may be substituted by 1 to 3 substituents, wherein the substituents independently of one another denote halogen (F, Cl, Br, I), (C1-4)alkyl, O—(C1-4)alkyl, CF3, OCF3 or NR19R20 (wherein R19 and R20 independently of one another denote H, methyl or acetyl); and
- R2 denotes H, (C1-4)alkyl, (C3-6)cycloalkyl, CH2COOH, —CH2C(O)NH2, OH or phenyl(C1-4)alkyl.
- The compounds according to the invention are valuable neurokinin (tachykinin) antagonists which have both substance P antagonism and also neurokinin-A- or neurokinin-B-antagonistic properties. They are useful for the treatment and prevention of neurokinin-mediated diseases.
- Compounds of general formula I may contain acid groups, mainly carboxyl groups, and/or basic groups such as amino functions, for example. Compounds of general formula I may therefore occur as internal salts, salts with pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, sulphonic acid or organic acids (such as, for example, maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically acceptable bases such as alkali metal or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as e.g. diethylamine, triethylamine, triethanolamine, etc.
- The compounds according to the invention may occur as racemates, but may also be obtained as pure enantiomers, i.e. in the (R) or (S) form. Compounds which occur as racemates or in the (S) form are preferred.
- Results of investigations into the compound according to the invention:
- The receptor affinity for the NK1 receptor (substance P receptor) is determined on human lymphoblastoma cells (IM-9) with cloned NK1 receptors, by measuring the displacement of 125I-labelled substance P. The Ki values thus obtained show the efficacy of the compounds.
Example no. Ki [nMol/L] 1 0.45 2 0.30 3 0.20 4 0.53 5 6.28 6 0.88 7 1.45 8 0.19 9 0.14 10 0.12 12 0.32 27 1.11 28 4.16 29 0.87 30 0.17 31 8.96 32 0.20 33 13.25 34 0.37 35 0.78 - The compounds according to the invention are valuable neurokinin (tachykinin) antagonists which have both substance P antagonism and also neurokinin-A- or neurokinin-B-antagonistic properties. They are useful for the treatment and prevention of neurokinin-mediated diseases:
- For preventing or treating inflammatory or allergic diseases
- of the respiratory tract such as asthma, chronic bronchitis, hyperreactive respiratory tract, emphysema, rhinitis, cough,
- of the eyes, such as conjunctivitis and iritis,
- of the skin, such as dermatitis in contact eczema, urticaria, psoriasis, sunburn, insect bites, itching, sensitive or hypersensitive skin,
- of the gastro-intestinal tract such as gastric and duodenal ulcers, ulcerative colitis, Crohn's disease, irritable bowel, Hirschsprung's disease,
- of the joints, such as rheumatoid arthritis, reactive arthritis and Reiter syndrome;
- for treating diseases of the central nervous system, such as dementia, Alzheimer's disease, schizophrenia, psychoses, depression, headache (e.g. migraine or tension headaches), epilepsy; Parkinson's disease, stroke,
- for treating Herpes zoster and postherpetic pain, tumours, collagenoses, dysfunction of the urinary tract, haemorrhoids, nausea and vomiting, triggered by radiation or cytostatic therapy, for example, or movement and pain of all kinds.
- The invention therefore also relates to the use of the compounds according to the invention as curative agents and pharmaceutical preparations which contain these compounds. They are preferably used in humans. The compounds according to the invention may be administered by intravenous, subcutaneous, intramuscular, intraperitoneal or intranasal route, by inhalation, by transdermal route, if desired with the aid of iontophoresis or enhancers known from the literature, and by oral route.
- For parenteral administration the compounds of formula I or the physiologically acceptable salts thereof are brought into solution, suspension or emulsion, optionally with the substances conventionally used for this, such as solubilisers, emulsifiers or other adjuvants. Suitable solvents include, for example: water, physiological saline solutions or alcohols, e.g. ethanol, propandiol or glycerol, sugar solutions such as glucose or mannitol solutions or a mixture of different solvents.
- Moreover, the compounds may be administered by means of implants, e.g. of polylactide, polyglycolide or polyhydroxybutyric acid or intranasal preparations.
- Preferred compounds of general formula 1 are those wherein
- X denotes N—R3 or CH—R4, wherein
-
- wherein R5, R6 and R7 independently of one another denote H, alkyl, cycloalkyl, aryl, aralkyl, alkanoyl, benzoyl, dialkylamino, dialkylaminoalkyl, trialkylammoniumalkyl, cyano, alkyloxycarbonyl, aralkyloxycarbonyl, OH, O-alkyl or O-aryl,
- wherein the alkyl groups contain 1 to 4 carbon atoms, the cycloalkyl groups contain 3 to 6 carbon atoms, aryl denotes phenyl or phenyl substituted by methyl or halogen (F, Cl, Br, I);
- or R5 and R6 or R6 and R7 together form the group —(CH2)2—, —(CH2)3—, —(CH2)4—, —(CH2)5—or —(CH2)2 O(CH2)2;
-
- are as hereinbefore defined and
- R8=H, alkyl with 1 to 5 carbon atoms or cycloalkyl with 3 to 6 carbon atoms or
- R7+R8 together form the group —(CH2)2—, —(CH2)3—, —(CH2)4—, —(CH2)5— or —(CH2)2 O (CH2)2—;
- Y denotes CH2 or (CH2)2;
- Z denotes O or H2;
- Ar denotes unsubstituted or mono- to 5-substituted phenyl [wherein the substituents of the phenyl independently of one another denote halogen (F, Cl, Br, I), OH, (C1-C)alkyl, O—(C1-4)alkyl, CF3, OCF3 or NR9R10 (wherein R9 and R10 independently of one another denote H, methyl or acetyl)] or Ar is phenyl substituted by —OCH2O— or —O(CH2)2O—;
- R1 denotes phenyl(C1-C4)alkyl or phenyl(C1-C4)alkanoyl, wherein phenyl may be substituted by 1 to 3 substituents, wherein the substituents independently of one another denote halogen (F, Cl, Br, I), (C1-4)alkyl, O—(C1-4)alkyl, CF3, OCF3 or NR19R20 (wherein R19 and R20 independently of one another denote H, methyl or acetyl); and
- R2 denotes H, (C1-4)alkyl or (C3-6)cycloalkyl.
- Particularly preferred are those compounds wherein
-
- and R5 to R8, Z, Ar, R1 and R2 are as hereinbefore defined, and Y denotes CH2.
- Of these compounds, the preferred ones are those wherein Z is oxo, and/or
- Ar is unsubstituted phenyl, particularly those wherein
- Ar is phenyl mono- or disubstituted by halogen, preferably
- Ar is dichlorophenyl; and/or wherein R1 denotes substituted phenylacetyl (preferably 3, 4-di-trifluoromethylphenyl-acetyl) or wherein R1 is substituted phenylethyl, wherein the phenyl is substituted by 2 substituents which, independently of one another, denote halogen (F, Cl, Br, I), (C1-4)alkyl or CF3, particularly wherein the substituents of the phenyl are CF3, CH3 or F, (preferably wherein the two substituents of the phenyl are CF3); and/or wherein R2 is (C1-4)alkyl, preferably wherein R2 is methyl.
-
- One aspect of the invention relates to compounds of formula I wherein X denotes the group CR4, wherein
-
- wherein
- R5 , R6 , R7 and R8 independently of one another denote H, alkyl with 1 to 4 carbon atoms or cycloalkyl with 3 to 6 carbon atoms; or
- R7 and R8 together form the group (CH2)2, (CH2)3, (CH2)4 or (CH2)5. Compounds wherein R5 and R6 denote H and R7 and R8 together form the group (CH2)2 or those wherein R5 and R6 denote H and R7 and R8 are cyclohexyl are preferred.
- Another important aspect of the invention relates to compounds of formula I wherein X is the group NR3 wherein
-
- wherein
- R5 and R6 independently of one another denote H, alkyl with 1 to 4 carbon atoms, cycloalkyl with 3 to 6 carbon atoms, phenyl, or phenyl, benzyl or benzoyl substituted by methyl or halogen (F, Cl, Br, I), CN, alkyloxycarbonyl (wherein the alkyl group contains 1 to 4 carbon atoms), benzyloxycarbonyl, alkoxy with 1 to 4 carbon atoms or dialkylamine (wherein the alkyl groups contain 1 to 4 carbon atoms), R7 denotes H or alkyl with 1 to 4 carbon atoms;
- or R5 and R6 or R6 and R7 together form the group (CH2)2, (CH2)3, (CH2)4 or (CH2)5; or R6 and R7 together form the group —(CH)2—O—(CH2)2—.
- Of these compounds, the preferred ones are those wherein
- a) R5 and R6 independently of one another denote H, alkyl with 1 to 4 carbon atoms, cycloalkyl with 3 to 6 carbon atoms, phenyl, phenyl, benzyl or benzoyl substituted by methyl or halogen (F, Cl, Br, I);
- R7 is H or alkyl with 1 to 4 carbon atoms or R5 and R6 or R6 and R7 together form the group (CH2)2, (CH2)3, (CH2)4 or (CH2)5; or R6 and R7 together form the group —(CH2)2—O—(CH2)2—;
- b) R5 and R6 independently of one another denote H, alkyl with 1 to 4 carbon atoms, cyclohexyl, phenyl, methyl-substituted phenyl, benzyl or benzoyl;
- R7 is H or methyl; or
- R5 and R6 together form the group (CH2)2 or R6 and R7 together form the group (CH2)5 or —(CH)2—O—(CH2)2—;
- c) R5 denotes H, alkyl with 1 to 4 carbon atoms, cyclohexyl, methyl-substituted phenyl, benzyl or benzoyl;
- R6 denotes H, alkyl with 1 to 3 carbon atoms, cyclohexyl, phenyl, methyl-substituted phenyl or benzyl;
- R7 is H or methyl; or
- R5 and R6 together form the group —(CH2)2—or R6 and R7 together form the group (CH2)2—O—(CH2)2—;
- d) R5 and R6 independently of one another denote H, CH3, CH(CH3)2, phenyl or benzyl, R7 is H or CH3, or
- R5 and R6 together form the group —CH2CH2—or R6 and R7 together form the group —(CH2)2—O—(CH2)2—.
-
-
- The compounds may be prepared by methods known per se. Advantageous methods are shown and described in the diagrams which follow.
-
- wherein
-
-
- Method A:
- Piperazine having a protecting group in the 1 position is reacted with 2-halophenyl-acetate to obtain N-protected piperazinyl-phenylacetate. This is saponified under suitable conditions, e.g. with sodium hydroxide solution, to obtain the corresponding carboxylic acid. This is then linked to an amine according to the invention, e.g. N-methyl-3,5-bis-trifluoromethylphenethyl-amine, using a suitable coupling reagent such as TBTU. In the next step the protecting group is cleaved from the piperazine part of the molecule using a suitable cleaving reagent. In the last step of the reaction, the free piperazine-N is reacted with unsubstituted or substituted amino-iminomethanesulphonic acid (which is obtained for example by oxidation of the corresponding thiourea using H2O2) to obtain the desired guanidine.
- Compounds of the type in Examples 1-3 may advantageously be prepared by method A, for example.
-
- Method B:
- The same procedure is used as in method A, except that in the last step, the reaction is carried out with carbodiimides instead of the substituted methanesulphonic acid. These may be either N, N′-disubstituted carbodiimides or N, N, N′-trisubstituted carbodiimides, which are then used in the form of a salt, e.g. the iodide.
- The compounds of the type in Examples 4 to 7 may advantageously be prepared according to method B, for example.
-
- Method C:
- The same procedure is used as in method A, except that in the last step, instead of the substituted methanesulphonic acid, a substituted thiourea is reacted together with HgO.
- Compounds of the type in Example 9 may advantageously be prepared according to method C, for example.
-
-
- The reaction is carried out in an inert solvent in the presence of a base.
-
- Method D:
- Analogously to the last step in method A, first of all, piperazine protected in the 1 position is reacted with unsubstituted or substituted amino-iminomethanesulphonic acid. Other substituents may be introduced into the resulting guanidine by alkylation or acylation if required. In the next step the piperazine derivative is obtained with an unsubstituted piperazine-N by cleaving the protecting group with a cleaving reagent.
- The reactant for this piperazine derivative is obtained as shown on the right in Diagram 4. (R)-Mandelic acid is reacted with methanesulphonic acid halide to obtain the (R)-2-(methanesulphonyloxy)-acetic acid. This is then reacted with a coupling reagent and the correspondingly substituted phenethylamine to form the corresponding amide, or it is converted into the corresponding acid halide (e.g. with SOCl2/SO2Cl2) and then converted, with the suitably substituted phenethylamine, into the corresponding amide. In the last step the amide thus obtained is reacted with the piperazine derivative described above, whereupon a C—N bond is formed, with elimination of methanesulphonate, whilst at the same time the chiral centre is reversed. The reaction is carried out in an inert solvent such as e.g. DMF or acetonitrile in the presence of a base such as TEA or N-methylmorpholine, for example, at temperatures between 20° C. and 120° C. The reaction time is between 0.5 h and 48 h.
- Compounds of the type in Example 8 may advantageously be synthesised according to method D.
-
- The method is carried out analogously to method D. Compounds of the type in Example 36 may advantageously be synthesised according to Method E.
-
- (R,S)-1-Amidino-4-[2-phenylacetic acid-N-methyl-N-(3,5-bis-trifluoromethyl-phenyl-ethyl)-amide]-piperazine, dihydrochloride:
- 1.09 g of (R,S)-1-[2-phenylacetic acid-N-methyl-N-(3,5-bis-trifluoromethyl-phenylethl)-amide]-piperazine (2 mmol) were mixed with 5 ml of water, 5 ml of methanol, 1.1 g of K2CO3 (8 mmol) and 0.5 g of aminoimino-methanesulphonic acid (4 mmol) and stirred for 2 days at RT. The reaction mixture was diluted with water and extracted several times with EE and ether. The organic phases were combined, dried with MgSO4 and evaporated to dryness. The solid residue was chromatographed over silica gel and the fractions found to be uniform by DC were combined and evaporated to dryness. The residue was dissolved in methanol, mixed with ethereal HCl, evaporated to dryness, stirred with ether, suction filtered and dried. 80 mg of the compound of Example 1 are obtained (yield 7%).
- melting point: 128-138° C.
- FAB-MS: (M+H)+=516.4.
- Examples 2 and 3 were prepared analogously:
-
- melting point: 163-173° C.
- FAB-MS: (M+H)+=542.2.
-
- melting point: 69-79° C.
- FAB-MS: (M+H)+=530.2.
-
- 0.82 g of (R,S)-1-[2-phenylacetic acid-N-methyl-N-(3,5-bis-tifluoromethyl-phenylethyl)-amide]-piperazine were mixed with 20 ml of CH2Cl2, 0.5 ml of TEA and 0.215 g of N,N′-diisopropylcarbodiimide and the reaction mixture was stirred for 4 days at RT. It was then evaporated to dryness and the residue was chromatographed over silica gel. The fractions found to be uniform by DC were combined and concentrated by evaporation, the residue was taken up in methanol, mixed with ethereal HCl and again evaporated to dryness. The solid residue was stirred with ether, suction filtered and dried, to obtain 0.35 g of the compound of Example 4 as a racemate (yield 35%).
- melting point: 176-186° C. (decomp.)
- FAB-MS: (M+H)+=600.6.
- Examples 5 to 7 were prepared analogously to Example 4.
-
- melting point: 174-184° C. (decomp.)
- FAB-MS: (M+H)+=600.6.
-
- melting point: 145-158° C.
- [α]D 20=24,8° (DMSO)
-
- melting point: 182-188° C. (decomp.)
- FAB-MS: (M+H)+=680.3.
-
- Preparation of 1-(1-methyl-imidazolin-2-yl)-piperazine: 1.86 of Boc-piperazine were combined with 25 ml of water, 25 ml of methanol, 2.77 g of K2CO3 and 1.5 g of imidazoline-2-sulphonic acid and stirred for 2 days at RT. After dilution with water the mixture was extracted with EE and chromatographed over silica gel. 0.8 g of 1-(imidazolin-2-yl)-4-Boc-piperazine were obtained. This substance was combined with 6.2 ml of DMF and 136 mg of NaH dispersion (60%). After one hour, 0.214 ml of methyl iodide was added dropwise and the reaction mixture was left for three days at RT. It was combined with water, extracted with EE and chromatographed over silica gel. In this way, 0.47 g of 1-(1-methylimidazolin-2-yl)-4-Boc-piperazine was obtained, which was treated with 5 ml of 4N HCl in dioxane at RT. After one hour, the mixture was concentrated by evaporation, stirred with ether and evaporated to dryness in vacuo. 0.38 g of 1-(1-methyl-imidazolin-2-yl)piperazine dihydrochloride was thus obtained as a solid substance (yield 15%).
- 0.73 g of (R)-mandelic acid-O-methanesulphonate-N-methyl-N-(3,5-bistrifluoromethylphenylethyl)-amide was combined with 15 ml of DMF, 0.7 ml of TEA and 0.38 g of 1-(1-methyl-imidazolin-2-yl)-piperazine dihydrochloride and stirred for 3 h at 65° C. The reaction mixture was evaporated down, the residue was first treated with NaHCO3 solution and then extracted twice with EE. The organic phases were combined, concentrated by evaporation under reduced pressure and the residue was chromatographed over silica gel. The product thus obtained was dissolved in ether, washed with NaHCO3, and evaporated to dryness with MgSO4.
- The residue was dissolved in methanol, mixed with excess ethereal HCl and evaporated to dryness, to obtain 0.18 g of the compound of Example 8 (yield 19%).
- melting point: 115-1250° C.
- FAB-MS: (M+H)+=556.9.
-
- 0.31 g of N,N′-dimethylthiourea, 26 ml of CH2Cl2, 0.63 g of Na2SO4, 1.25 g of HgO, 0.77 g of (S)-1-[2-phenylacetic acid-N-methyl-N-(3,5-bistrifluoromethyl-phenylethyl)-amide]-piperazine and 0.42 ml of TEA were combined, stirred for 3 days at RT and then refluxed for 4 hours. The reaction mixture was concentrated by evaporation under reduced pressure and the residue was treated with water and EE. The organic phase separated off was filtered and evaporated to dryness. The residue was chromatographed over silica gel. The eluate obtained was evaporated down, dissolved in methanol, mixed with ethereal HCl, evaporated to dryness once more, the residue was washed with ether and dried. 0.15 g of the compound of Example 9 was obtained as a white solid (yield 16%).
- melting point: 126-1400° C.
- FAB-MS: (M+H)+=543.8.
-
- melting point: 131-141° C.
- [α]D 20=20.6° (DMSO)
- The Examples which follow may be prepared using the methods described.
-
- (+)-enantiomer melting point: 171-181 ° C.
- [α]20/D=28.4° (DMSO).
-
- melting point: 240-245° C. (decomp.)
- FAB-MS: (M+H)+=592.1.
-
-
- (+)-enantiomer FAB-MS: (M+H)+=584.
-
-
-
-
-
-
-
-
-
-
-
-
- melting point: 124-1280° C. FAB-MS: (M+H)+=648.2
-
- melting point: 193-198° FAB-MS: (M+H)+=696.4
- [a]D 20=+50.0° (DMSO)
-
- melting point: 146-149° [α]D 20=+48.8° (DMSO)
-
- melting point: 90-100° [α]D 20=+23.6° (DMSO)
-
- melting point: 170-180° FAB-MS: (M+H)+=661.9
-
- melting point: 84-94° [α]D 20=20.4° (DMSO)
-
- melting point: 169-179° [α]D 20=43.6° (DMSO)
-
- melting point: 131-141° [α]D 20=+25.2° (DMSO)
-
- melting point:146 - 148° FAB-MS: (M+H)+=584, 586, 588
-
- melting point: 126-134° C.
- 3.8g of 4-amino-1-benzylpiperidine (20 mmol) was combined with 4.7 g of dicyclohexylcarbodiimide (23 mmol) in 80 ml of DMF and stirred for 12 hours at 80° C. The solvent was evaporated in vacuo and the residue was flash-chromatographed using ethyl acetate/methanol (1:1) whereby 54.g of 1-benzyl-4(N′, N″-dicyclohexyl-guanidino)-piperidine was obtained (71%). 5 g of the product (12.6 mmol) was dissolved in 60 ml of methanol and hydrogenated using 0.6 g of Pd(C) at 2 bar hydrogen pressure. Thus obtained was 4 g of 4(N′, N″-dicyclohexyl-guanidino)-piperidine (63%)
- 2.14 g of the product (7 mmol) was combined with 2.9 g of (R)-2-methylsulphonyloxy-N-methyl-N-[2-(3,5-bistrifluoromethyl-phenyl)-ethyl]-phenylacetamide (6 mmol), 60 ml of DMF and 0.96 ml of triethylamine and stirred for 3 hours at 65° C. The residue obtained after concentrating the raw product was chromatographed over silica gel with ethyl acetate/methanol (1:1) as an eluant, whereupon 0.6 g of the desired substance was obtained.
-
- melting point: 114-124° C.
- [α]20/D=41.4° (DMSO).
Pharmaceutical preparations: Injectable solution 200 mg of active substance* 1.2 mg of monopotassium dihydrogen phosphate = KH2PO4 0.2 mg of disodium hydrogen phosphate {close oversize brace} (buffer) = NaH2PO4.2H2O 94 mg of sodium chloride or {close oversize brace} (for an isotonic solution) 520 mg of glucose 4 mg of albumin (protease protection) q.s. sodium hydroxide solution {close oversize brace} ad pH 6 q.s. hydrochloric acid ad 10 ml water for injections Injectable solution 200 mg of active substance* 94 mg of sodium chloride or 520 mg of glucose 4 mg of albumin q.s. sodium hydroxide solution {close oversize brace} ad pH 9 q.s. hydrochloric acid ad 10 ml water for injections Lyophilisate 200 mg of active substance* 520 mg of mannitol (for isotonic solution/bulking agent) 4 mg of albumin solvent 1 for lyophilisate 10 ml water for injections solvent 2 for lyophilisate 20 mg Polysorbate ®80 = Tween ®80 (surfactant) 10 ml water for injections - Dosage for person weighing 67 kg: 1 to 500 mg
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US10/085,818 US20020147359A1 (en) | 1998-05-30 | 2002-02-25 | Intermediate compound for preparing guanidine and amidine derivatives |
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DE19824470A DE19824470A1 (en) | 1998-05-30 | 1998-05-30 | Novel neurokine antagonists, processes for their preparation and pharmaceutical compositions containing these compounds |
DE198.24.470.3 | 1998-05-30 | ||
US09/320,974 US6103719A (en) | 1998-05-30 | 1999-05-27 | Neurokinin antagonists, processes for preparing them and pharmaceutical compositions containing these compounds |
US09/897,664 US6429328B2 (en) | 1998-05-30 | 2001-07-02 | Processes and intermediate compounds for preparing guanidine and amidine derivatives |
US10/085,818 US20020147359A1 (en) | 1998-05-30 | 2002-02-25 | Intermediate compound for preparing guanidine and amidine derivatives |
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US09/566,754 Expired - Fee Related US6277840B1 (en) | 1998-05-30 | 2000-05-09 | Neurokinin antagonists, processes for preparing them and pharmaceutical compositions containing these compounds |
US09/897,664 Expired - Lifetime US6429328B2 (en) | 1998-05-30 | 2001-07-02 | Processes and intermediate compounds for preparing guanidine and amidine derivatives |
US10/085,818 Abandoned US20020147359A1 (en) | 1998-05-30 | 2002-02-25 | Intermediate compound for preparing guanidine and amidine derivatives |
US10/085,592 Expired - Lifetime US6455700B1 (en) | 1998-05-30 | 2002-02-27 | Process for preparing guanidine and amidine derivatives |
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US09/566,754 Expired - Fee Related US6277840B1 (en) | 1998-05-30 | 2000-05-09 | Neurokinin antagonists, processes for preparing them and pharmaceutical compositions containing these compounds |
US09/897,664 Expired - Lifetime US6429328B2 (en) | 1998-05-30 | 2001-07-02 | Processes and intermediate compounds for preparing guanidine and amidine derivatives |
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US6413959B1 (en) | 1995-04-14 | 2002-07-02 | Boehringer Ingelheim Kg | Method of treating depression with arylglycinamide derivatives |
US6291514B1 (en) * | 1998-02-09 | 2001-09-18 | 3-Dimensional Pharmaceuticals, Inc. | Heteroaryl amidines, methylamidines and guanidines, preparation thereof, and use thereof as protease inhibitors |
DE19824470A1 (en) * | 1998-05-30 | 1999-12-02 | Boehringer Ingelheim Pharma | Novel neurokine antagonists, processes for their preparation and pharmaceutical compositions containing these compounds |
US6875759B1 (en) | 1999-07-21 | 2005-04-05 | Kadmus Pharmaceuticals | Substituted guanidines and the use thereof |
CA2412355A1 (en) * | 2000-06-12 | 2001-12-20 | University Of Rochester | Method of treating symptoms of hormonal variation, including hot flashes, using tachykinin receptor antagonist |
UA75093C2 (en) | 2000-10-06 | 2006-03-15 | Dimensional Pharm Inc | Aminopyridinyl-,aminoguanidinyl-, and alkoxyguanidinesubstituted phenylsubstituted phenylacetamides as protease inhibitors |
BRPI0413555A (en) | 2003-08-18 | 2006-10-17 | Lundbeck & Co As H | compound or salt thereof, pharmaceutical composition, use of a compound or salt, and method for treating a disease, for the manufacture of a compound and for the preparation of compound |
WO2005100325A1 (en) * | 2004-04-14 | 2005-10-27 | Astrazeneca Ab | Aryl glycinamide derivatives and their use as nk1 antagonists and serotonin reuptake inhibithors |
TWI376373B (en) | 2005-02-16 | 2012-11-11 | Lundbeck & Co As H | Crystalline base of a pharmaceutical compound |
TWI453198B (en) | 2005-02-16 | 2014-09-21 | Lundbeck & Co As H | Process for making the trans-1-( (1r , 3s)- 6-chloro - 3 -phenylindan-1- yl ) - 3 , 3 - dimethylpiperazine and salts thereof and for making 4 -((1r , 3s )-6- chloro- 3- phenylindan -1- yl )-1, 2 , 2 -trimethylpiperazine and salts thereof |
CN101641099A (en) | 2007-01-24 | 2010-02-03 | 葛兰素集团有限公司 | Pharmaceutical compositions comprising 3, 5-diamin0-6- (2, 3-dichl0phenyl) -l, 2, 4-triazine or r (-) -2, 4-diamino-5- (2, 3-dichlorophenyl) -6-fluoromethyl pyrimidine and an nk1 |
JP2011519873A (en) * | 2008-05-07 | 2011-07-14 | ハー・ルンドベック・アクチエゼルスカベット | How to treat cognitive deficits |
DE102015104299A1 (en) * | 2015-03-23 | 2016-09-29 | International Automotive Components Group Gmbh | Interior trim part for a motor vehicle |
HUE057044T2 (en) | 2015-04-07 | 2022-04-28 | Ela Pharma Ltd | Compositions for treating and/or preventing cell or tissue necrosis specifically targeting cathepsin c and/or cela1 and/or cela3a and/or structurally related enzymes thereto |
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CA1173037A (en) * | 1980-03-01 | 1984-08-21 | John L. Archibald | Piperidino ureas as antidepressants |
US5364943A (en) * | 1991-11-27 | 1994-11-15 | Pfizer Inc. | Preparation of substituted piperidines |
TW201303B (en) * | 1990-07-05 | 1993-03-01 | Hoffmann La Roche | |
US5607936A (en) * | 1994-09-30 | 1997-03-04 | Merck & Co., Inc. | Substituted aryl piperazines as neurokinin antagonists |
DE19519245C2 (en) * | 1995-04-14 | 2003-04-30 | Boehringer Ingelheim Kg | Novel arylglycine amide derivatives, processes for their preparation and pharmaceutical compositions containing them |
TW449590B (en) * | 1995-04-14 | 2001-08-11 | Boehringer Ingelheim Kg | New arylglycinamide derivatives, processes for the manufacture thereof and pharmaceutical compositions containing these compounds |
US5795894A (en) * | 1995-05-02 | 1998-08-18 | Schering Corporation | Piperazino derivatives as neurokinn antagonists |
US5654316A (en) * | 1995-06-06 | 1997-08-05 | Schering Corporation | Piperidine derivatives as neurokinin antagonists |
DE19608665A1 (en) * | 1996-03-06 | 1997-09-11 | Boehringer Ingelheim Kg | Novel arylglycine amide derivatives, processes for their preparation and pharmaceutical compositions containing them |
DE19824470A1 (en) * | 1998-05-30 | 1999-12-02 | Boehringer Ingelheim Pharma | Novel neurokine antagonists, processes for their preparation and pharmaceutical compositions containing these compounds |
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- 1998-05-30 DE DE19824470A patent/DE19824470A1/en not_active Withdrawn
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1999
- 1999-05-22 JP JP2000552105A patent/JP2002517386A/en active Pending
- 1999-05-22 CA CA002333689A patent/CA2333689A1/en not_active Abandoned
- 1999-05-22 WO PCT/EP1999/003531 patent/WO1999062893A2/en not_active Application Discontinuation
- 1999-05-22 EP EP99926368A patent/EP1086088A2/en not_active Withdrawn
- 1999-05-27 US US09/320,974 patent/US6103719A/en not_active Expired - Fee Related
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2000
- 2000-05-09 US US09/566,754 patent/US6277840B1/en not_active Expired - Fee Related
-
2001
- 2001-07-02 US US09/897,664 patent/US6429328B2/en not_active Expired - Lifetime
-
2002
- 2002-02-25 US US10/085,818 patent/US20020147359A1/en not_active Abandoned
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US6455700B1 (en) | 2002-09-24 |
US6429328B2 (en) | 2002-08-06 |
US6103719A (en) | 2000-08-15 |
EP1086088A2 (en) | 2001-03-28 |
US20020010173A1 (en) | 2002-01-24 |
US20020133012A1 (en) | 2002-09-19 |
US6277840B1 (en) | 2001-08-21 |
WO1999062893A3 (en) | 2000-03-09 |
CA2333689A1 (en) | 1999-12-09 |
JP2002517386A (en) | 2002-06-18 |
WO1999062893A2 (en) | 1999-12-09 |
DE19824470A1 (en) | 1999-12-02 |
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