CA2166903C - 3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them - Google Patents
3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing themInfo
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- CA2166903C CA2166903C CA002166903A CA2166903A CA2166903C CA 2166903 C CA2166903 C CA 2166903C CA 002166903 A CA002166903 A CA 002166903A CA 2166903 A CA2166903 A CA 2166903A CA 2166903 C CA2166903 C CA 2166903C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
- C07D231/28—Two oxygen or sulfur atoms
- C07D231/30—Two oxygen or sulfur atoms attached in positions 3 and 5
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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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
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- 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
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
- C07D231/16—Halogen atoms or nitro radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The present invention relates to new pyrazole derivatives possessing an amide group substituted with an amino acid or one of its derivatives at position 3 and variously substituted in positions 1, 2, 4 or 5 of the pyrazole ring, to a process for preparing these and to pharmaceutical compositions containing the said pyrazole derivatives as an active ingredient. The novel compounds are capable of binding to neurotensin receptor and are capable of beng useful in pathological states associated with dysfunction of the dopaminergic systems. The novel compounds comprise a 3-amidopyrazole of formula I:
<See fig. I>
in which:
X is hydrogen;
X' is a C3-C7 cycloalkyl group; or X and X', together with the carbon atom to which they are linked, form a C3-C12 cycloalkyl group optionally substituted by a C1-C3 alkyl;
R1 represents:
a phenyl group substituted by Ra, R'a and R"a wherein Ra, R'a and R"a each independently represent a hydrogen atom, a halogen atom, a hydroxyl, a linear or branched C1-C4 alkyl group, a C1-C4 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a nitro group, a carboxyl group or an amino group;
a tetrahydronaphthyl group;
a naphthyl group substituted by Ra, R'a and R"a as defined above; or a quinolyl or isoquinolyl group optionally substituted by Ra, R'a and R"a as defined above;
R represents hydrogen or linear or branched C1-C4 alkyl;
n represents 0, 1, 2 or 3;
Z represents a hydroxyl group;
a C1-C6 alkoxy group;
an oxygen atom substituted with a carboxylic acid-protecting group, wherein the carboxylic acid-protecting group is selected from the group consisting of tert-butyl, benzyl, benzyl substituted with a halogen atom, C1-C6 alkyl, trifluoromethyl, trifluoromethoxy or carboxyl;
an amino group; or a nitrogen atom substituted with a carboxyalkyl in which the alkyl is a linear or branched C1-C6 group;
RIV represents a hydrogen atom, a halogen atom or a C1-C6 alkyl;
RV represents:
a phenyl group substituted by R5, R'5 and R"5, where R5, R'5 and R"5 each independently represent a hydrogen atom, a halogen atom, a linear or branched C1-C4 alkyl, a hydroxyl, a C1-C4 alkoxy, a nitro, a trifluoromethyl, a trifluoromethoxy, a cyano, an amino, a carboxyl, a C1-C4 carboxyalkyl or a phenyl;
a naphthyl group unsubstituted or substituted with a C1-C4 alkyl;
a pyridyl group;
a styryl group unsubstituted or substituted with a C1-C4 alkyl;
or alternatively RIV and RV considered together represent:
a group in which the phenyl group substitutes the pyrazole at position 5 and the group -(CH2)i - in which i = 1 to 3 substitutes the pyrazole at position 4; W1 W2 and W3 substitute the benzene ring and independently represent hydrogen, a halogen or a hydroxyl group;
or one of its possible salts with organic or inorganic acids or with inorganic or organic bases.
<See fig. I>
in which:
X is hydrogen;
X' is a C3-C7 cycloalkyl group; or X and X', together with the carbon atom to which they are linked, form a C3-C12 cycloalkyl group optionally substituted by a C1-C3 alkyl;
R1 represents:
a phenyl group substituted by Ra, R'a and R"a wherein Ra, R'a and R"a each independently represent a hydrogen atom, a halogen atom, a hydroxyl, a linear or branched C1-C4 alkyl group, a C1-C4 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a nitro group, a carboxyl group or an amino group;
a tetrahydronaphthyl group;
a naphthyl group substituted by Ra, R'a and R"a as defined above; or a quinolyl or isoquinolyl group optionally substituted by Ra, R'a and R"a as defined above;
R represents hydrogen or linear or branched C1-C4 alkyl;
n represents 0, 1, 2 or 3;
Z represents a hydroxyl group;
a C1-C6 alkoxy group;
an oxygen atom substituted with a carboxylic acid-protecting group, wherein the carboxylic acid-protecting group is selected from the group consisting of tert-butyl, benzyl, benzyl substituted with a halogen atom, C1-C6 alkyl, trifluoromethyl, trifluoromethoxy or carboxyl;
an amino group; or a nitrogen atom substituted with a carboxyalkyl in which the alkyl is a linear or branched C1-C6 group;
RIV represents a hydrogen atom, a halogen atom or a C1-C6 alkyl;
RV represents:
a phenyl group substituted by R5, R'5 and R"5, where R5, R'5 and R"5 each independently represent a hydrogen atom, a halogen atom, a linear or branched C1-C4 alkyl, a hydroxyl, a C1-C4 alkoxy, a nitro, a trifluoromethyl, a trifluoromethoxy, a cyano, an amino, a carboxyl, a C1-C4 carboxyalkyl or a phenyl;
a naphthyl group unsubstituted or substituted with a C1-C4 alkyl;
a pyridyl group;
a styryl group unsubstituted or substituted with a C1-C4 alkyl;
or alternatively RIV and RV considered together represent:
a group in which the phenyl group substitutes the pyrazole at position 5 and the group -(CH2)i - in which i = 1 to 3 substitutes the pyrazole at position 4; W1 W2 and W3 substitute the benzene ring and independently represent hydrogen, a halogen or a hydroxyl group;
or one of its possible salts with organic or inorganic acids or with inorganic or organic bases.
Description
~166gO~
3-AMIDOP~R~OLE DERIVAT-V.-, PROCESS FOR
PREPA IN~- THE E AND PH~ MACEUTICAL
COMP~ ITIONS CONTAI~_NG TH:M
The present invention relates to new pyrazole derivatives possessing an amide group substituted with an amino acid or one of its derivatives at position 3 and variously substituted in positions 1, 2, 4 or 5 of the pyrazole ring, to a process for preparing these and to pharmaceutical compositions containing the said pyrazole derivatives as an active ingredient.
This application is a division of copending Canadian Patent Application No. 2,049,514 filed August 20, 1991.
The compounds according to the invention possess activity with respect to the central nervous system, the cardiovascular system or the gastrointestinal system.
A large number of pyrazole derivatives are described in the literature.
1,5-Diarylpyrazoles substituted at position 3 with an alkyl chain containing from 2 to 16 carbon atoms and variously substituted, in particular with an amide, and corresponding to the formula:
A ~ ~ (CH2~-CON ~ 3 A! ¦ A2 n=2 to 16 'f /11 ~\'1 A1 (A) are described in European Patent 0,248,594 as possessing anti-inflammatory activity and activity with respect to the cardiovascular system.
Pyrazole derivatives of formula:
21~5903 B~5 B15 CONHB3 B 5 N~ ~B2 (B) where B2 represents either a hydrogen atom or a methyl group, B3 represents, for example, an alkyl and B5, B'5 and B"5 independently represent, for example, hydrogen, a halogen or a C1-C3 alkoxy, are described in British Patent 2,130,205 as being capable of use for the purpose of decreasing the blood uric acid level in mammals.
It is, moreover, described in Journal of the Chemical Society, 1973, 2532-2534 that 2-morpholino-5-phenyl-5-phenylazofuran salts rearrange to 1,5-diphenylpyrazoles substituted at position 3, of formula:
CO-N O
,N
b~l (C) Patent Application WO 89/02,431 describes new N-containing heterocyclic, in particular pyrazolyl, compounds of formula:
,(C~2~, ,R1 B N ~ R2 R6 O (D) - 2166~3 in which, for example:
- Ar represents a pyrazolyl, - B represents (CH2)m with m = 0 to 4, - Z represents -C=O, n = 1 to 3, - D represents COR3, - R1 and R2 represent a hydrogen or a C1-C8 alkyl or together go to make up a cyclic amine.
These amidopyrazole amide derivatives of acyl-glutamic or -aspartic acid are described as possessing cholecystokinin-inhibiting properties.
It has now been found that variously substituted derivatives of 3-amidopyrazole possess activity with respect to the central nervous system, and especially with respect to the neuropeptide-regulating systems, displacing, for example, tritiated or iodinated neurotensin from its receptor.
Thus, the subject of the present invention, according to one of its aspects, is a 3-amidopyrazole of formula (I) or (I'):
RIV f ~ (C~2,n ~ z RV ,N
IN tI) RI
RIV f N-(CH2)n- 1 -Il-z RV N~N~ (T~ ) in which 6gO3 ~ RI represents R~
R"
. a group ~ ~
~~~Y - R~, where Ra/ R~ a and Rl'a each independently represent a hydrogen atom, a halogen atom, a hydroxyl, a linear or branched C1-C4 alkyl group, a C1-C4 alkoxy group, a trifluoromethyl group, a tri-fluoromethoxy group, a nitro group, a carboxyl group or an amino group;
~ a carboxyalkyl or alkoxycarbonylalkyl group in which the alkyls are Cl-C4 groups;
~ a cycloalkyl group in which the alkyls are C3-C6 groups;
~ a tetrahydronaphthyl group;
~ a pyridyl group;
~ a naphthyl group substituted with Ra~ R' a and R~a as defined above;
~ a benzyl group substituted with Ra~ R' a and R'la as defined above;
~ a cinnamyl group optionally substituted on the aromatic ring with a halogen, a hydroxyl or a Cl-C4 alkoxy;
~ a quinolyl or isoquinolyl group optionally substituted with Ra~ R' a and R~a as defined above;
~ a 2-benzothiazolyl group;
~ a quinoxalinyldione group;
~ a 1-phthalazinyl group;
~ a benzothiadiazolyl group;
~ a methylene group substituted with a 5- or 6-membered heterocyclic group such as, in particular, a pyridyl and a thienyl;
-2166gO3 - RIa represents a benzyl group substituted with R
R' a and R~a as defined above;
- R represents hydrogen or a linear or branched C1-C4 alkyl;
- n represents 0, 1, 2 or 3;
- either X represents hydrogen and X' represents hydrogen; a linear or branched Cl-C6 alkyl; an aryl; a C1-C4 aminoalkyl; a C1-C4 hydroxyalkyl; a carboxyalkyl in which the alkyl group is a C1-C4 group; an acetamidoalkylcysteine in which the alkyl group is a C1-C4 group; a guanidinoalkyl in which the alkyl group is a C1-C4 group; a nitroguanidinoalkyl in which the alkyl group is a C1-C4 group; a C3-C7 cycloalkyl; an arylalkyl in which the alkyl is a C1-C4 group and in which the aryl is optionally substituted with a halogen or a hydroxyl or with a Cl-C3 alkyl; a heteroarylalkyl in which the heteroaryl represents an imidazolyl or an indolyl unsubstituted or substituted with a C1-C4 alkyl, with a hydroxyl or with a C1-C4 alkoxy and in which the alkyl is a C1-C4 group;
- or, when n is equal to zero, X represents hydrogen and X' and -N-R considered together form a ring, unsubstituted or substituted with a hydroxyl, of formula:
--~ C~--H2C~j/ (CH2)m-2 (HO) with m = 2,3 or 4 or a ring-system of formula:
N ~
with t = 1 or 2 ~16~ 903 or a ring-system of formula:
~ ~ with t = l or 2 l(CH2)t or an indolinyl, perhydroindole or 4,5,6,7-tetrahydro-thieno[2,3-c]pyrid-6-yl ring-system;
- or X and X' each independently represent a C1-C4 alkyl or a C3-C6 cycloalkyl; a phenyl;
- or X and X' are linked and form together a cyclo-alkyl group having 2 to 12 carbon atoms, optionally substituted with a Cl-C3 alkyl;
- or X, X' and the carbon atom to which they are linked form an adamantylidene group; an adamantylidene group substituted with one or two methyl groups or with a hydroxyl, a C1-C3 alkoxy or a halogen atom; a 1-azaadamantyl group; a quinuclidinyl group; a 4-piperidyl group optionally N-substituted with a benzyl group; a 2,2,6,6-tetramethylpiperidyl group; a tetrahydronaphthyl group; a tetrahydropyran-4-yl or tetrahydrothiopyran-4-yl group; a 2,3-dihydro-4H-benzopyran-4-yl group; a 2,3-dihydro-4H-benzothiopyran-4-yl group; a group of formula a (C7~lF ~
~C H 2 ) n ~7 H, ) n 3 in which n1 = O or 1, n'1 = 1 or 2, n2 = 1, n3 = 2 or 3 and W represents a carbon atom or an oxygen atom, this 21~03 R
I
group of formula a) being attached to -N- and to -C(O)-Z as defined above through one carbon atom of one or other of the rings, or a group of formula b (cH<?2)~
in which n4 = 2, 3 or 4, n5 = 2 or 3 and W represents a carbon or oxygen atom, this group of formula b) being R
attached to -N- and to -C(O)-Z as defined above through one carbon atom of one or other of the two rings, it being possible for the rings of the above groups a and b to be optionally substituted on one and/or other of the rings with one or two Cl-C4 alkyl groups and it not being possible for the amino acid to be at the alpha-position with respect to W when W represents oxygen; a bicyclo[2.2.1]hept-5-en-2-yl group; an 8-oxabicyclo[3.2.1]oct-6-en-3-yl group; an 8-thiabicyclo-[3.2.1]oct-3-yl group;
- or X represents hydrogen and X' is an adamantyl group; an adamantyl group substituted with one or two methyls, with a hydroxyl, a Cl-C3 alkoxy or a halogen atom; a l-azaadamantyl group; a group of formula a or b as defined above, it not being possible for the bond between these ring-systems and the carbon carrying -COZ and -N-R to be at the alpha-position with respect to W when the latter represents oxygen;
.
- Z represents a hydroxyl group or a C1-C6 alkoxy group; an oxygen atom substituted with a carboxylic acid-protecting group such as a tert-butyl, a benzyl, a benzyl substituted with a halogen atom, a C1-C6 alkyl, a trifluoromethyl, a trifluoromethoxy or a carboxyl group; an amino group; a nitrogen atom substituted with a carboxyalkyl in which the alkyl is a linear or branched C1-C6 group, with the limitation that, if Z represents a nitrogen atom substituted as defined above and if n = 0, then, when X = H, X' cannot be a group:
(CH2) X-C-Q
O
in which x = 1 or 2 and Q is a hydroxyl, a free amino or amino substituted with a C1-C6 dialkyl or a C1-C6 alkoxy;
- RIV represents a hydrogen atom, a halogen atom or a C1-C6 alkyl;
- RV represents:
R~
a group ~ -R'S
R~S
where R5, R~ 5, and R~5 each independently represent a hydrogen atom, a halogen atom, a linear or branched C1-C4 alkyl, a hydroxyl, a C1-C4 alkoxy, a nitro, a trifluoromethyl, a trifluoromethoxy, a cyano, an amino, a carboxyl, a C1-C4 carboxyalkyl or a phenyl;
- a naphthyl group unsubstituted or substituted with a Cl-C4 alkyl;
- a pyridyl group;
- a styryl group unsubstituted or substituted with a Cl-C4 alkyl;
~1669()3 - or alternatively RIV and RV considered together represent:
CH2) 1 a group w~ W2 in which the phenyl group substitutes the pyrazole at position 5 and the group -(CH2)i- in which i = 1 to 3 substitutes the pyrazole at position 4, W1, W2 and W3 substitute the benzene ring and independently represent hydrogen, a halogen or a hydroxyl group;
or one of its possible salts with organic or inorganic acids or with inorganic or organic bases.
In accordance with the present invention, there are claimed only:
The compounds of formula (I) in which:
- X is hydrogen;
15 ~ X' is a (C3-C7) cycloalkyl group; or - X and X' together with the carbon atom to which they are linked form a (C3-Cl2) cycloalkyl group optionally substituted by a (C1-C3) alkyl;
~ RI represents:
~ a phenyl group substituted by Rl, R'1 and R"1;
~ a tetrahydronaphthyl group;
~ a naphthyl group substituted by R1, R'1 and R"1;
~ a quinolyl or isoquinolyl group substituted by R1, R'1 and R 1.
No claim is made herein to any other compounds of formula (I).
In the present description, "aryl" denotes aromatic rings such as, for example, phenyl.
When the compounds (I) or (I') include an 30 asymmetric carbon, the enantiomers form part of the invention.
9a When the compounds (I) or (I') contain a group of formula a) or b), the cycloaliphatic amino acids comprise both those for which the amine function is in 2166 ~03 the endo position with respect to the aliphatic ring system and those for which the amine function is in the exo position with respect to the aliphatic ring system.
The possible salts of the products of formula (I) or (I') according to the present invention comprise both those with inorganic or organic acids which permit an appropriate crystallisation or separation of the compounds of formula (I) or (I'), such as picric acid or oxalic acid, and those which form pharmaceutically acceptable salts such as the hydrochloride, hydrobromide, sulphate, hydrogen sulphate, dihydrogen phosphate, methanesulphonate, methyl sulphate, maleate, fumarate and 2-naphthalenesulphonate.
The possible salts of the products of formula (I) or (I') also comprise the salts with cations, for example the alkali metal or alkaline earth metal salts such as the sodium, potassium and calcium salts, the sodium salt being preferred, when the said product of formula (I) or (I') contains a carboxylic acid group.
A particular class of the compounds of the invention consists of the compounds of formula (I) or (I') in which RI is either a naphthyl group or a phenyl group substituted with Ra~ R' a and R'la as defined above, the other substituents being as defined above.
Another preferred group of the compounds of the invention consists of the compounds of formula (I) or (I') in which RV represents a naphthyl or phenyl group substituted with R5, R' 5 and R~5 as defined above, the other substituents being as defined above. Preferably, R5, R~ 5 or R~5 is hydrogen or a C1-C4 alkoxy.
Another preferred group of the compounds of the invention consists of the compounds of formula (I) or (I') in which R, Z, n, RIV and RV are as above defined and X, X' and the carbon atom to which they are linked ~16603 -form an adamantylidene group, a group of formula a or of formula _ as above defined.
According to another of its aspects, the present invention relates to a process for the preparation of the compounds of formula (I) and (I'), characterized in that a functional derivative of formula (II) or (II'):
R,~ P'I R V R r, (II) (II~) in which RI~ RIV~ RV and RIa are as defined above, is treated with an amino acid, optionally protected by the protective groups customary in peptide synthesis, of formula:
X' I I
HN--(CH2)n--C-- Icl-- Z (V) X O
in which R, n, X, X' and Z are as defined above or optionally protected.
As a functional derivative of the pyrazolecar-boxylic acid of formula (II) or (II'), it is possibleto use the acid chloride, the anhydride, a mixed anhydride, an ester, an activated ester, for example the p-nitrophenyl ester, or the free acid judiciously activated, for example, with N,N-dicyclohexylcarbodi-imide or with benzotriazolyl-N-oxytris(dimethylamino) phosphonium hexafluorophosphate (BOP).
The compounds (I) and (I') thus prepared may then be deprotected, where appropriate, to yield the corresponding free acids.
, The esters (IIa) and (II'a) which are precursors of the carboxylic acids (II) and (II'), defined above, are synthesised by applying the method described in Chem. Pharm. Bull, 1984, 32, 4, 1577.
The process for preparing the compounds (I) or (I') via the esters (IIa) and (II'a) is represented by the following scheme:
sr~M~ 1 ~~) N~G) R b)co2~, CH30H /C~
co2~ RV CO ~ CH 3 (Ir~
Rl NHNH2 ~ ~2H4 H'~
C ) Rl VC02CH3 ~C~2cH3 R 1~ C02CH3 RV lN~N RV ~'~ 2 ) R~E rRI~E R N
H
(IIa) d) (II'a) R ~ COOH R~COOH
Dr ~ ) or (~ ) (II') The first step a) consists in the preparation of the sodium enolates of a ketone of formula 1, in which Rv and RIV are as defined above, which are reacted with an equimolar amount of ethyl oxalate (step b)) in an alkanol such as, for example, methanol, according to L.
CLAISEN, Ber., 1909, 42, 59. After precipitation in ethyl ether, the sodium enolates (III) are separated by filtration.
The sodium enolates (III) thus prepared and an excess of hydrazine or of a hydrazine derivative RI-NHNH2 are then heated to reflux of acetic acid (step c) ) .
In the case where RI represents a substituted or unsubstituted benzyl group RIa, there is obtained, during the condensation of the benzylhydrazine with the compounds (III), a mixture, in variable proportions depending on the nature and position of the substituents of RV~ of the compounds (IIa) and its isomer (II'a) of formula:
~ V CO2CH~
~ a) RV R I
in which RIa~ RIV and RV are as defined above.
The two isomers (IIa) and (II'a) may then be separated by column chromatography. On saponification of the esters, the pure isomeric acids are obtained, which acids are reacted, for example, with sulphinyl chloride. The acid chlorides are then condensed with the amino acids of formula (V) to yield the compounds (I) and (I') according to the invention (step e)).
A variant of the process, in the case where RI is a benzyl or cinnamyl group, consists in the condensation of unsubstituted hydrazine with the 21 6690~
compound (III) (step c')) to yield the lH-pyrazole derivative (IV), which is then substituted in the presence of NaH or NaNH2 with a group RIE or RIaE (step c")), where E represents a group which can be eliminated such as a halogen, a p-toluenesulphonyloxy (tosyloxy) or a methanesulphanyloxy (mesyloxy).
The 3-amidopyrazole derivatives (I) and (I') which are subjects of the invention are then prepared from the pyrazole acids by converting the ester derivatives (IIa) and (II'a) to their corresponding acids (II) or (II') by the action of an alkaline agent such as, for example, potassium hydroxide, followed by acidification (step d), then the corresponding compounds of formula (I) and (I') are prepared as described above.
If the amino acid contains a hydroxyl group as a substituent, the latter may be protected by an O-protecting group customarily used, and then deprotected according to the usual methods.
When the product of formula (I) or (I') possesses a basic function and is obtained in the form of a free base, the salification is performed by treatment with the chosen acid in an organic solvent. On treatment of the free base, dissolved, for example in an alcohol such as isopropanol, with a solution of the chosen acid in the same solvent, the corresponding salt is obtained, which salt is isolated according to conventional techniques. Thus, for example, the hydrochloride, hydrobromide, sulphate, hydrogen sulphate, dihydrogen phosphate, methanesulphonate, methyl sulphate, oxalate, maleate, fumarate or 2-naphthalenesulphonate is prepared.
When the compound of formula (I) or (I') possesses a basic function and is isolated in the form of one of its salts, for example the hydrochloride or oxalate, the free base may be prepared by neutralisation of the said salt with an inorganic or organic base such as sodium hydroxide or triethylamine, or with an alkali metal carbonate or bicarbonate such as sodium or potassium carbonate or bicarbonate.
When the product of formula (I) or (I') contains an acid group, the compound thereby obtained may be converted to a metal salt, in particular an alkali-metal salt such as the sodium salt, or an alkaline earth metal salt such as the calcium salt, according to conventional processes.
The compounds (I) or (I') according to the invention were subjected to biochemical tests.
The same compounds (I) or (I') and their salts displace, at concentrations of less than one micro-molar,[Tyr3-iodinated] neurotensin from its receptor on guinea pig brain membranes, according to the method described by SADOUL J.L. et al., Biochemical and Biophysical Research Commllnications~ 1984, 120, 3, 812-819.
The compounds of the present invention are of low toxicity; in particular, their acute toxicity is compatible with their use as a medicinal product. For such a use, an effective amount of a compound of formula (I) or (I') or of one of their pharmaceutically acceptable salts is administered to mammals.
The compounds (I) or (I') according to the invention are the first potential non-peptide synthetic medicinal products capable of binding to the neuro-tensin receptor and capable of being useful in pathological states associated with a dysfunction of the dopaminergic systems, for example as antipsychotics (D.R. HANDRICH et al., Brain Research, 1982, 231, 216-221 and C.B. NEMEROFF, Biological Psychiatry, 1980, 15-2, 283-302), and in disorders of the cardiovascular or gastrointestinal system.
Thus, the subject of the present invention, according to another of its aspects, is pharmaceutical compositions containing as active principles the compounds of formula (I) or (I') or their possible pharmaceutically acceptable salts.
In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intra-muscular, intravenous, transdermal or rectal admini-stration, the active principles may be administered, in unit dosage forms, as a mixture or with conventional pharmaceutical excipients, to animals and human beings.
The appropriate unit dosage forms comprise forms for oral administration such as tablets, gelatin capsules, powders, granules and oral solutions or suspensions, forms for sublingual and buccal administration, forms for subcutaneous, intramuscular or intravenous administration and forms for rectal administration.
In order to obtain the desired effect, the dose of active principle can vary between 1 and 1,000 mg per day, and preferably between 2 and 500 mg.
Each unit dose can contain from 1 to 250 mg of active principle, and preferably from 2 to 125 mg, in combination with a pharmaceutical vehicle. This unit dose may be administered 1 to 4 times per day.
When a solid composition is prepared in the form of tablets, the active principle is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. It is possible to coat the tablets with sucrose or with other suitable substances, or they may alternatively be treated in such a way that they have a sustained or delayed activity and release a predetermined amount of active principle in continuous fashion.
- ~166~03 A gelatin capsule preparation is obtained by mixing the active principle with a diluent and pouring the mixture obtained into soft or hard gelatin capsules.
A preparation in the form of syrup or elixir can contain the active principle together with a sweetener, preferably a zero-calorie sweetener, and methylparaben and propylparaben as antiseptic, as well as an agent imparting flavour and a suitable colouring.
The water-dispersible powders or granules can contain the active principle mixed with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone and the like, as well as with sweeteners or flavour correctors.
For rectal administration, suppositories are employed, which are prepared with binders melting at rectal temperature, for example cocoa butter or polyethylene glycols.
For parenteral administration, aqueous suspen-sions, isotonic saline solutions or sterile and injectable solutions are used, which contain pharma-cologically compatible dispersing and/or wetting agents, for example propylene glycol or butylene glycol.
The active principle may also be formulated in the form of microcapsules, optionally with one or more excipients or additives.
The examples which follow illustrate the invention without, however, limiting it.
The instantaneous melting points (m.p.) of the crystallised products were measured on a Kofler heating stage and are expressed in degrees Celsius. In the tables which follow, the following abbreviations have been used:
CH cyclohexane CH2Cl2 dichloromethane EtOH ethanol Et2O diethyl ether 5 Hx hexane Pn pentane iPr2O diisopropyl ether iPrOH isopropanol AcOEt ethyl acetate 10 MeOH methanol C* means configuration of the asymmetric carbon.
The following abbreviations are used in the NMR
spectra:
M multiplet 15 S singlet BS broad singlet D doublet Har aromatic H
o : ortho; m : meta PREPARATION OF THE SYNTHESIS INTERMEDIATES
A. Preparation of the hydrazine derivatives .(RINHNH2).
A large number of hydrazine derivatives were commercial products.
The others were prepared according to known methods by diazotisation of the corresponding aromatic amine followed by reduction of the diazonium salt. Thus, as an example, the preparation of the following may be mentioned:
- 5,6,7,8-tetrahydro-l-naphthylhydrazine, according to R. FUSCO et al., Gazz. Chim. Ital., 1974, 104, 813-817;
- 8-hydrazinoquinoline, according to A. ALBERT et al., J. Chem. Soc., 1967, 1533-1541;
- 2166~03 - 5-hydrazionquinoline and 5-hydrazinoisoquino-line, according to M.G. FERLIN et al., Il Farmaco, 1989, 44 (12), 1141-1155.
B. Preparation of the pyrazolecarboxylic acids (II):
R lV COO~l Rr This preparation is carried out according to the above described method.
Table A below shows, as an example and without implied limitation, the characteristics of acids of formula (II).
~u~ A
RS ~COOH
~ N
RI R5 R's M.P.;~C
~ ~ OCH3 OCH3 ~02 CH3 CH3 ~250 OC~3 OCH3 211 OC2Hs OC2H5 262 OCH3 OCH3 2~0 Q
~. 21~6gO3 OCH3 OCH3 ~41 OCH3 OC~3 >260 >~60 CN~H3 OCH3 (~cco,.l~o~on) ~N
C. Prepsration of the amino acids.
The non-commercial products are prepared according to the ST~FrR~R synthesis (Ann., 75, 27, 1850) or according to the synthesis of H.T. ~u~n~ER et al., J. Pract. Chem., 1934, 141, 5, followed by a hydrolysis to yield the amino acids; for example, 2-amino-2-adamant~necArho~ylic acid is prepared according to H.T. NASANTA et al., J. Med. C.~.em., 1973, 16 (7), 823.
~ inocyclo~l~Anecarboxylic acids are prepa~ed according to J.W. TSANG et al., J. Med. Chem., 1984, 27, 1663.
(R)- and (S)-Cyclo~e--Lylglycines are prepared by resolution of benzyloxycsrbonylcyclopentylglyc~r.e.
1) Preparation of racemic benzyloxyc2rbonylcyclo-pentylglycine This compound is prepared by the follow ng reaction scheme 2.
SCU~M~ 2 ~ < C02Me THF
JOC 1988~ K HB- H C02Me Pd/C 10%
AcOH
.SN ~Cl ~ re~ux 4hou.s p H2N C02H, Ha /\
HN C02Me O H
C6H5CH2~fi-NaOH, H20 ~Z
C6H5-CH2-~~ NH C02H
2) (RS)-Cyclopentylglycine h~ochloride.
80% NaH (1.8 g) is dissolved in anhydrous THF
(50 ml). A mixture of cyclopentanone (4.2 g) and methyl isocyanoacetate (5 g) in THF (50 ml) is added dropwise and with stirring. When the addition i8 complete, the mixture is left for 2 hours. It is cooled to 5~C and acetic ac-d n 10%
aqueous solution (50 ml) is added slowly. The THF
o is evaporated off under vacuum. The aqueous residue i8 extracted with chloroform (3 x 120 ml). The organic phase is dried over NazSO4 and concentrated under vacuum.
The residue is taken up with pentane, filtered off and wa~hed with pentane.
The solid (7.6 g) is dissolved in acetic zc d (100 ml). Palladium on charcoal (10% Pd) (3 g) is added and the mixture is stirred at atmospheric pres~ure and room temperature under hyd~ogen for 24 hours (1 litre of hydrogen is absorbed). The mixture is filtered through Celite*, whlch is washed several time~ with acetic acid. The filtrate is evaporated under vacuum. The residue o is taken up in 5.5 N l-ydlochloric acid (70 ml).
The mixture i~ heated to reflux for 4 hou-3. It is concentrated to dryness, and the res due s treated azeotropically with toluene several t:~e~
and dried under vacuum. The expected product is obtAine~.
m = 7.2 g NMR D20: 8 H at 1.6 (M, ring CH2); 1 H at 2.20 (~, ring CH); 1 H at 3.80 (D,J-7 C~CO~R); 3 H at 8.60 (BS, NH3 ) 3) Acylation with benzyl chloroformate.
(RS)-Cyclopentylglycine hydl~chloride (7.2 g) is dissolved in 2 N sodium hydroxide solution (65 ml). Benzyl chloroformate (8.5 g) in THF
(30 ml) i8 added dropwise, cooling to 5~C. The 2s mixture is left stirring overnight at room temperature. It i8 cooled in ice. It is acidified with concentrated HCl to pH 2 (T s 5-C). It i8 extracted with chloroform and the organic phase is dried and evaporated. The residue is t~ken up with pentane. (RS)-Benzyloxyc~rhonylcyclopenLy-glycine is obtAine~.
~.p. llO-C
3-AMIDOP~R~OLE DERIVAT-V.-, PROCESS FOR
PREPA IN~- THE E AND PH~ MACEUTICAL
COMP~ ITIONS CONTAI~_NG TH:M
The present invention relates to new pyrazole derivatives possessing an amide group substituted with an amino acid or one of its derivatives at position 3 and variously substituted in positions 1, 2, 4 or 5 of the pyrazole ring, to a process for preparing these and to pharmaceutical compositions containing the said pyrazole derivatives as an active ingredient.
This application is a division of copending Canadian Patent Application No. 2,049,514 filed August 20, 1991.
The compounds according to the invention possess activity with respect to the central nervous system, the cardiovascular system or the gastrointestinal system.
A large number of pyrazole derivatives are described in the literature.
1,5-Diarylpyrazoles substituted at position 3 with an alkyl chain containing from 2 to 16 carbon atoms and variously substituted, in particular with an amide, and corresponding to the formula:
A ~ ~ (CH2~-CON ~ 3 A! ¦ A2 n=2 to 16 'f /11 ~\'1 A1 (A) are described in European Patent 0,248,594 as possessing anti-inflammatory activity and activity with respect to the cardiovascular system.
Pyrazole derivatives of formula:
21~5903 B~5 B15 CONHB3 B 5 N~ ~B2 (B) where B2 represents either a hydrogen atom or a methyl group, B3 represents, for example, an alkyl and B5, B'5 and B"5 independently represent, for example, hydrogen, a halogen or a C1-C3 alkoxy, are described in British Patent 2,130,205 as being capable of use for the purpose of decreasing the blood uric acid level in mammals.
It is, moreover, described in Journal of the Chemical Society, 1973, 2532-2534 that 2-morpholino-5-phenyl-5-phenylazofuran salts rearrange to 1,5-diphenylpyrazoles substituted at position 3, of formula:
CO-N O
,N
b~l (C) Patent Application WO 89/02,431 describes new N-containing heterocyclic, in particular pyrazolyl, compounds of formula:
,(C~2~, ,R1 B N ~ R2 R6 O (D) - 2166~3 in which, for example:
- Ar represents a pyrazolyl, - B represents (CH2)m with m = 0 to 4, - Z represents -C=O, n = 1 to 3, - D represents COR3, - R1 and R2 represent a hydrogen or a C1-C8 alkyl or together go to make up a cyclic amine.
These amidopyrazole amide derivatives of acyl-glutamic or -aspartic acid are described as possessing cholecystokinin-inhibiting properties.
It has now been found that variously substituted derivatives of 3-amidopyrazole possess activity with respect to the central nervous system, and especially with respect to the neuropeptide-regulating systems, displacing, for example, tritiated or iodinated neurotensin from its receptor.
Thus, the subject of the present invention, according to one of its aspects, is a 3-amidopyrazole of formula (I) or (I'):
RIV f ~ (C~2,n ~ z RV ,N
IN tI) RI
RIV f N-(CH2)n- 1 -Il-z RV N~N~ (T~ ) in which 6gO3 ~ RI represents R~
R"
. a group ~ ~
~~~Y - R~, where Ra/ R~ a and Rl'a each independently represent a hydrogen atom, a halogen atom, a hydroxyl, a linear or branched C1-C4 alkyl group, a C1-C4 alkoxy group, a trifluoromethyl group, a tri-fluoromethoxy group, a nitro group, a carboxyl group or an amino group;
~ a carboxyalkyl or alkoxycarbonylalkyl group in which the alkyls are Cl-C4 groups;
~ a cycloalkyl group in which the alkyls are C3-C6 groups;
~ a tetrahydronaphthyl group;
~ a pyridyl group;
~ a naphthyl group substituted with Ra~ R' a and R~a as defined above;
~ a benzyl group substituted with Ra~ R' a and R'la as defined above;
~ a cinnamyl group optionally substituted on the aromatic ring with a halogen, a hydroxyl or a Cl-C4 alkoxy;
~ a quinolyl or isoquinolyl group optionally substituted with Ra~ R' a and R~a as defined above;
~ a 2-benzothiazolyl group;
~ a quinoxalinyldione group;
~ a 1-phthalazinyl group;
~ a benzothiadiazolyl group;
~ a methylene group substituted with a 5- or 6-membered heterocyclic group such as, in particular, a pyridyl and a thienyl;
-2166gO3 - RIa represents a benzyl group substituted with R
R' a and R~a as defined above;
- R represents hydrogen or a linear or branched C1-C4 alkyl;
- n represents 0, 1, 2 or 3;
- either X represents hydrogen and X' represents hydrogen; a linear or branched Cl-C6 alkyl; an aryl; a C1-C4 aminoalkyl; a C1-C4 hydroxyalkyl; a carboxyalkyl in which the alkyl group is a C1-C4 group; an acetamidoalkylcysteine in which the alkyl group is a C1-C4 group; a guanidinoalkyl in which the alkyl group is a C1-C4 group; a nitroguanidinoalkyl in which the alkyl group is a C1-C4 group; a C3-C7 cycloalkyl; an arylalkyl in which the alkyl is a C1-C4 group and in which the aryl is optionally substituted with a halogen or a hydroxyl or with a Cl-C3 alkyl; a heteroarylalkyl in which the heteroaryl represents an imidazolyl or an indolyl unsubstituted or substituted with a C1-C4 alkyl, with a hydroxyl or with a C1-C4 alkoxy and in which the alkyl is a C1-C4 group;
- or, when n is equal to zero, X represents hydrogen and X' and -N-R considered together form a ring, unsubstituted or substituted with a hydroxyl, of formula:
--~ C~--H2C~j/ (CH2)m-2 (HO) with m = 2,3 or 4 or a ring-system of formula:
N ~
with t = 1 or 2 ~16~ 903 or a ring-system of formula:
~ ~ with t = l or 2 l(CH2)t or an indolinyl, perhydroindole or 4,5,6,7-tetrahydro-thieno[2,3-c]pyrid-6-yl ring-system;
- or X and X' each independently represent a C1-C4 alkyl or a C3-C6 cycloalkyl; a phenyl;
- or X and X' are linked and form together a cyclo-alkyl group having 2 to 12 carbon atoms, optionally substituted with a Cl-C3 alkyl;
- or X, X' and the carbon atom to which they are linked form an adamantylidene group; an adamantylidene group substituted with one or two methyl groups or with a hydroxyl, a C1-C3 alkoxy or a halogen atom; a 1-azaadamantyl group; a quinuclidinyl group; a 4-piperidyl group optionally N-substituted with a benzyl group; a 2,2,6,6-tetramethylpiperidyl group; a tetrahydronaphthyl group; a tetrahydropyran-4-yl or tetrahydrothiopyran-4-yl group; a 2,3-dihydro-4H-benzopyran-4-yl group; a 2,3-dihydro-4H-benzothiopyran-4-yl group; a group of formula a (C7~lF ~
~C H 2 ) n ~7 H, ) n 3 in which n1 = O or 1, n'1 = 1 or 2, n2 = 1, n3 = 2 or 3 and W represents a carbon atom or an oxygen atom, this 21~03 R
I
group of formula a) being attached to -N- and to -C(O)-Z as defined above through one carbon atom of one or other of the rings, or a group of formula b (cH<?2)~
in which n4 = 2, 3 or 4, n5 = 2 or 3 and W represents a carbon or oxygen atom, this group of formula b) being R
attached to -N- and to -C(O)-Z as defined above through one carbon atom of one or other of the two rings, it being possible for the rings of the above groups a and b to be optionally substituted on one and/or other of the rings with one or two Cl-C4 alkyl groups and it not being possible for the amino acid to be at the alpha-position with respect to W when W represents oxygen; a bicyclo[2.2.1]hept-5-en-2-yl group; an 8-oxabicyclo[3.2.1]oct-6-en-3-yl group; an 8-thiabicyclo-[3.2.1]oct-3-yl group;
- or X represents hydrogen and X' is an adamantyl group; an adamantyl group substituted with one or two methyls, with a hydroxyl, a Cl-C3 alkoxy or a halogen atom; a l-azaadamantyl group; a group of formula a or b as defined above, it not being possible for the bond between these ring-systems and the carbon carrying -COZ and -N-R to be at the alpha-position with respect to W when the latter represents oxygen;
.
- Z represents a hydroxyl group or a C1-C6 alkoxy group; an oxygen atom substituted with a carboxylic acid-protecting group such as a tert-butyl, a benzyl, a benzyl substituted with a halogen atom, a C1-C6 alkyl, a trifluoromethyl, a trifluoromethoxy or a carboxyl group; an amino group; a nitrogen atom substituted with a carboxyalkyl in which the alkyl is a linear or branched C1-C6 group, with the limitation that, if Z represents a nitrogen atom substituted as defined above and if n = 0, then, when X = H, X' cannot be a group:
(CH2) X-C-Q
O
in which x = 1 or 2 and Q is a hydroxyl, a free amino or amino substituted with a C1-C6 dialkyl or a C1-C6 alkoxy;
- RIV represents a hydrogen atom, a halogen atom or a C1-C6 alkyl;
- RV represents:
R~
a group ~ -R'S
R~S
where R5, R~ 5, and R~5 each independently represent a hydrogen atom, a halogen atom, a linear or branched C1-C4 alkyl, a hydroxyl, a C1-C4 alkoxy, a nitro, a trifluoromethyl, a trifluoromethoxy, a cyano, an amino, a carboxyl, a C1-C4 carboxyalkyl or a phenyl;
- a naphthyl group unsubstituted or substituted with a Cl-C4 alkyl;
- a pyridyl group;
- a styryl group unsubstituted or substituted with a Cl-C4 alkyl;
~1669()3 - or alternatively RIV and RV considered together represent:
CH2) 1 a group w~ W2 in which the phenyl group substitutes the pyrazole at position 5 and the group -(CH2)i- in which i = 1 to 3 substitutes the pyrazole at position 4, W1, W2 and W3 substitute the benzene ring and independently represent hydrogen, a halogen or a hydroxyl group;
or one of its possible salts with organic or inorganic acids or with inorganic or organic bases.
In accordance with the present invention, there are claimed only:
The compounds of formula (I) in which:
- X is hydrogen;
15 ~ X' is a (C3-C7) cycloalkyl group; or - X and X' together with the carbon atom to which they are linked form a (C3-Cl2) cycloalkyl group optionally substituted by a (C1-C3) alkyl;
~ RI represents:
~ a phenyl group substituted by Rl, R'1 and R"1;
~ a tetrahydronaphthyl group;
~ a naphthyl group substituted by R1, R'1 and R"1;
~ a quinolyl or isoquinolyl group substituted by R1, R'1 and R 1.
No claim is made herein to any other compounds of formula (I).
In the present description, "aryl" denotes aromatic rings such as, for example, phenyl.
When the compounds (I) or (I') include an 30 asymmetric carbon, the enantiomers form part of the invention.
9a When the compounds (I) or (I') contain a group of formula a) or b), the cycloaliphatic amino acids comprise both those for which the amine function is in 2166 ~03 the endo position with respect to the aliphatic ring system and those for which the amine function is in the exo position with respect to the aliphatic ring system.
The possible salts of the products of formula (I) or (I') according to the present invention comprise both those with inorganic or organic acids which permit an appropriate crystallisation or separation of the compounds of formula (I) or (I'), such as picric acid or oxalic acid, and those which form pharmaceutically acceptable salts such as the hydrochloride, hydrobromide, sulphate, hydrogen sulphate, dihydrogen phosphate, methanesulphonate, methyl sulphate, maleate, fumarate and 2-naphthalenesulphonate.
The possible salts of the products of formula (I) or (I') also comprise the salts with cations, for example the alkali metal or alkaline earth metal salts such as the sodium, potassium and calcium salts, the sodium salt being preferred, when the said product of formula (I) or (I') contains a carboxylic acid group.
A particular class of the compounds of the invention consists of the compounds of formula (I) or (I') in which RI is either a naphthyl group or a phenyl group substituted with Ra~ R' a and R'la as defined above, the other substituents being as defined above.
Another preferred group of the compounds of the invention consists of the compounds of formula (I) or (I') in which RV represents a naphthyl or phenyl group substituted with R5, R' 5 and R~5 as defined above, the other substituents being as defined above. Preferably, R5, R~ 5 or R~5 is hydrogen or a C1-C4 alkoxy.
Another preferred group of the compounds of the invention consists of the compounds of formula (I) or (I') in which R, Z, n, RIV and RV are as above defined and X, X' and the carbon atom to which they are linked ~16603 -form an adamantylidene group, a group of formula a or of formula _ as above defined.
According to another of its aspects, the present invention relates to a process for the preparation of the compounds of formula (I) and (I'), characterized in that a functional derivative of formula (II) or (II'):
R,~ P'I R V R r, (II) (II~) in which RI~ RIV~ RV and RIa are as defined above, is treated with an amino acid, optionally protected by the protective groups customary in peptide synthesis, of formula:
X' I I
HN--(CH2)n--C-- Icl-- Z (V) X O
in which R, n, X, X' and Z are as defined above or optionally protected.
As a functional derivative of the pyrazolecar-boxylic acid of formula (II) or (II'), it is possibleto use the acid chloride, the anhydride, a mixed anhydride, an ester, an activated ester, for example the p-nitrophenyl ester, or the free acid judiciously activated, for example, with N,N-dicyclohexylcarbodi-imide or with benzotriazolyl-N-oxytris(dimethylamino) phosphonium hexafluorophosphate (BOP).
The compounds (I) and (I') thus prepared may then be deprotected, where appropriate, to yield the corresponding free acids.
, The esters (IIa) and (II'a) which are precursors of the carboxylic acids (II) and (II'), defined above, are synthesised by applying the method described in Chem. Pharm. Bull, 1984, 32, 4, 1577.
The process for preparing the compounds (I) or (I') via the esters (IIa) and (II'a) is represented by the following scheme:
sr~M~ 1 ~~) N~G) R b)co2~, CH30H /C~
co2~ RV CO ~ CH 3 (Ir~
Rl NHNH2 ~ ~2H4 H'~
C ) Rl VC02CH3 ~C~2cH3 R 1~ C02CH3 RV lN~N RV ~'~ 2 ) R~E rRI~E R N
H
(IIa) d) (II'a) R ~ COOH R~COOH
Dr ~ ) or (~ ) (II') The first step a) consists in the preparation of the sodium enolates of a ketone of formula 1, in which Rv and RIV are as defined above, which are reacted with an equimolar amount of ethyl oxalate (step b)) in an alkanol such as, for example, methanol, according to L.
CLAISEN, Ber., 1909, 42, 59. After precipitation in ethyl ether, the sodium enolates (III) are separated by filtration.
The sodium enolates (III) thus prepared and an excess of hydrazine or of a hydrazine derivative RI-NHNH2 are then heated to reflux of acetic acid (step c) ) .
In the case where RI represents a substituted or unsubstituted benzyl group RIa, there is obtained, during the condensation of the benzylhydrazine with the compounds (III), a mixture, in variable proportions depending on the nature and position of the substituents of RV~ of the compounds (IIa) and its isomer (II'a) of formula:
~ V CO2CH~
~ a) RV R I
in which RIa~ RIV and RV are as defined above.
The two isomers (IIa) and (II'a) may then be separated by column chromatography. On saponification of the esters, the pure isomeric acids are obtained, which acids are reacted, for example, with sulphinyl chloride. The acid chlorides are then condensed with the amino acids of formula (V) to yield the compounds (I) and (I') according to the invention (step e)).
A variant of the process, in the case where RI is a benzyl or cinnamyl group, consists in the condensation of unsubstituted hydrazine with the 21 6690~
compound (III) (step c')) to yield the lH-pyrazole derivative (IV), which is then substituted in the presence of NaH or NaNH2 with a group RIE or RIaE (step c")), where E represents a group which can be eliminated such as a halogen, a p-toluenesulphonyloxy (tosyloxy) or a methanesulphanyloxy (mesyloxy).
The 3-amidopyrazole derivatives (I) and (I') which are subjects of the invention are then prepared from the pyrazole acids by converting the ester derivatives (IIa) and (II'a) to their corresponding acids (II) or (II') by the action of an alkaline agent such as, for example, potassium hydroxide, followed by acidification (step d), then the corresponding compounds of formula (I) and (I') are prepared as described above.
If the amino acid contains a hydroxyl group as a substituent, the latter may be protected by an O-protecting group customarily used, and then deprotected according to the usual methods.
When the product of formula (I) or (I') possesses a basic function and is obtained in the form of a free base, the salification is performed by treatment with the chosen acid in an organic solvent. On treatment of the free base, dissolved, for example in an alcohol such as isopropanol, with a solution of the chosen acid in the same solvent, the corresponding salt is obtained, which salt is isolated according to conventional techniques. Thus, for example, the hydrochloride, hydrobromide, sulphate, hydrogen sulphate, dihydrogen phosphate, methanesulphonate, methyl sulphate, oxalate, maleate, fumarate or 2-naphthalenesulphonate is prepared.
When the compound of formula (I) or (I') possesses a basic function and is isolated in the form of one of its salts, for example the hydrochloride or oxalate, the free base may be prepared by neutralisation of the said salt with an inorganic or organic base such as sodium hydroxide or triethylamine, or with an alkali metal carbonate or bicarbonate such as sodium or potassium carbonate or bicarbonate.
When the product of formula (I) or (I') contains an acid group, the compound thereby obtained may be converted to a metal salt, in particular an alkali-metal salt such as the sodium salt, or an alkaline earth metal salt such as the calcium salt, according to conventional processes.
The compounds (I) or (I') according to the invention were subjected to biochemical tests.
The same compounds (I) or (I') and their salts displace, at concentrations of less than one micro-molar,[Tyr3-iodinated] neurotensin from its receptor on guinea pig brain membranes, according to the method described by SADOUL J.L. et al., Biochemical and Biophysical Research Commllnications~ 1984, 120, 3, 812-819.
The compounds of the present invention are of low toxicity; in particular, their acute toxicity is compatible with their use as a medicinal product. For such a use, an effective amount of a compound of formula (I) or (I') or of one of their pharmaceutically acceptable salts is administered to mammals.
The compounds (I) or (I') according to the invention are the first potential non-peptide synthetic medicinal products capable of binding to the neuro-tensin receptor and capable of being useful in pathological states associated with a dysfunction of the dopaminergic systems, for example as antipsychotics (D.R. HANDRICH et al., Brain Research, 1982, 231, 216-221 and C.B. NEMEROFF, Biological Psychiatry, 1980, 15-2, 283-302), and in disorders of the cardiovascular or gastrointestinal system.
Thus, the subject of the present invention, according to another of its aspects, is pharmaceutical compositions containing as active principles the compounds of formula (I) or (I') or their possible pharmaceutically acceptable salts.
In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intra-muscular, intravenous, transdermal or rectal admini-stration, the active principles may be administered, in unit dosage forms, as a mixture or with conventional pharmaceutical excipients, to animals and human beings.
The appropriate unit dosage forms comprise forms for oral administration such as tablets, gelatin capsules, powders, granules and oral solutions or suspensions, forms for sublingual and buccal administration, forms for subcutaneous, intramuscular or intravenous administration and forms for rectal administration.
In order to obtain the desired effect, the dose of active principle can vary between 1 and 1,000 mg per day, and preferably between 2 and 500 mg.
Each unit dose can contain from 1 to 250 mg of active principle, and preferably from 2 to 125 mg, in combination with a pharmaceutical vehicle. This unit dose may be administered 1 to 4 times per day.
When a solid composition is prepared in the form of tablets, the active principle is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. It is possible to coat the tablets with sucrose or with other suitable substances, or they may alternatively be treated in such a way that they have a sustained or delayed activity and release a predetermined amount of active principle in continuous fashion.
- ~166~03 A gelatin capsule preparation is obtained by mixing the active principle with a diluent and pouring the mixture obtained into soft or hard gelatin capsules.
A preparation in the form of syrup or elixir can contain the active principle together with a sweetener, preferably a zero-calorie sweetener, and methylparaben and propylparaben as antiseptic, as well as an agent imparting flavour and a suitable colouring.
The water-dispersible powders or granules can contain the active principle mixed with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone and the like, as well as with sweeteners or flavour correctors.
For rectal administration, suppositories are employed, which are prepared with binders melting at rectal temperature, for example cocoa butter or polyethylene glycols.
For parenteral administration, aqueous suspen-sions, isotonic saline solutions or sterile and injectable solutions are used, which contain pharma-cologically compatible dispersing and/or wetting agents, for example propylene glycol or butylene glycol.
The active principle may also be formulated in the form of microcapsules, optionally with one or more excipients or additives.
The examples which follow illustrate the invention without, however, limiting it.
The instantaneous melting points (m.p.) of the crystallised products were measured on a Kofler heating stage and are expressed in degrees Celsius. In the tables which follow, the following abbreviations have been used:
CH cyclohexane CH2Cl2 dichloromethane EtOH ethanol Et2O diethyl ether 5 Hx hexane Pn pentane iPr2O diisopropyl ether iPrOH isopropanol AcOEt ethyl acetate 10 MeOH methanol C* means configuration of the asymmetric carbon.
The following abbreviations are used in the NMR
spectra:
M multiplet 15 S singlet BS broad singlet D doublet Har aromatic H
o : ortho; m : meta PREPARATION OF THE SYNTHESIS INTERMEDIATES
A. Preparation of the hydrazine derivatives .(RINHNH2).
A large number of hydrazine derivatives were commercial products.
The others were prepared according to known methods by diazotisation of the corresponding aromatic amine followed by reduction of the diazonium salt. Thus, as an example, the preparation of the following may be mentioned:
- 5,6,7,8-tetrahydro-l-naphthylhydrazine, according to R. FUSCO et al., Gazz. Chim. Ital., 1974, 104, 813-817;
- 8-hydrazinoquinoline, according to A. ALBERT et al., J. Chem. Soc., 1967, 1533-1541;
- 2166~03 - 5-hydrazionquinoline and 5-hydrazinoisoquino-line, according to M.G. FERLIN et al., Il Farmaco, 1989, 44 (12), 1141-1155.
B. Preparation of the pyrazolecarboxylic acids (II):
R lV COO~l Rr This preparation is carried out according to the above described method.
Table A below shows, as an example and without implied limitation, the characteristics of acids of formula (II).
~u~ A
RS ~COOH
~ N
RI R5 R's M.P.;~C
~ ~ OCH3 OCH3 ~02 CH3 CH3 ~250 OC~3 OCH3 211 OC2Hs OC2H5 262 OCH3 OCH3 2~0 Q
~. 21~6gO3 OCH3 OCH3 ~41 OCH3 OC~3 >260 >~60 CN~H3 OCH3 (~cco,.l~o~on) ~N
C. Prepsration of the amino acids.
The non-commercial products are prepared according to the ST~FrR~R synthesis (Ann., 75, 27, 1850) or according to the synthesis of H.T. ~u~n~ER et al., J. Pract. Chem., 1934, 141, 5, followed by a hydrolysis to yield the amino acids; for example, 2-amino-2-adamant~necArho~ylic acid is prepared according to H.T. NASANTA et al., J. Med. C.~.em., 1973, 16 (7), 823.
~ inocyclo~l~Anecarboxylic acids are prepa~ed according to J.W. TSANG et al., J. Med. Chem., 1984, 27, 1663.
(R)- and (S)-Cyclo~e--Lylglycines are prepared by resolution of benzyloxycsrbonylcyclopentylglyc~r.e.
1) Preparation of racemic benzyloxyc2rbonylcyclo-pentylglycine This compound is prepared by the follow ng reaction scheme 2.
SCU~M~ 2 ~ < C02Me THF
JOC 1988~ K HB- H C02Me Pd/C 10%
AcOH
.SN ~Cl ~ re~ux 4hou.s p H2N C02H, Ha /\
HN C02Me O H
C6H5CH2~fi-NaOH, H20 ~Z
C6H5-CH2-~~ NH C02H
2) (RS)-Cyclopentylglycine h~ochloride.
80% NaH (1.8 g) is dissolved in anhydrous THF
(50 ml). A mixture of cyclopentanone (4.2 g) and methyl isocyanoacetate (5 g) in THF (50 ml) is added dropwise and with stirring. When the addition i8 complete, the mixture is left for 2 hours. It is cooled to 5~C and acetic ac-d n 10%
aqueous solution (50 ml) is added slowly. The THF
o is evaporated off under vacuum. The aqueous residue i8 extracted with chloroform (3 x 120 ml). The organic phase is dried over NazSO4 and concentrated under vacuum.
The residue is taken up with pentane, filtered off and wa~hed with pentane.
The solid (7.6 g) is dissolved in acetic zc d (100 ml). Palladium on charcoal (10% Pd) (3 g) is added and the mixture is stirred at atmospheric pres~ure and room temperature under hyd~ogen for 24 hours (1 litre of hydrogen is absorbed). The mixture is filtered through Celite*, whlch is washed several time~ with acetic acid. The filtrate is evaporated under vacuum. The residue o is taken up in 5.5 N l-ydlochloric acid (70 ml).
The mixture i~ heated to reflux for 4 hou-3. It is concentrated to dryness, and the res due s treated azeotropically with toluene several t:~e~
and dried under vacuum. The expected product is obtAine~.
m = 7.2 g NMR D20: 8 H at 1.6 (M, ring CH2); 1 H at 2.20 (~, ring CH); 1 H at 3.80 (D,J-7 C~CO~R); 3 H at 8.60 (BS, NH3 ) 3) Acylation with benzyl chloroformate.
(RS)-Cyclopentylglycine hydl~chloride (7.2 g) is dissolved in 2 N sodium hydroxide solution (65 ml). Benzyl chloroformate (8.5 g) in THF
(30 ml) i8 added dropwise, cooling to 5~C. The 2s mixture is left stirring overnight at room temperature. It i8 cooled in ice. It is acidified with concentrated HCl to pH 2 (T s 5-C). It i8 extracted with chloroform and the organic phase is dried and evaporated. The residue is t~ken up with pentane. (RS)-Benzyloxyc~rhonylcyclopenLy-glycine is obtAine~.
~.p. llO-C
4) Resolution of benzyloxyc~rhsnylcyclo~en~ylglycine.
BenzyloxycArbonylcyclopentylglycine (5.54 g) i8 dis~olved in abQolute ethanol (65 ml).
(-)-(lR,2S,)-1,2-Diphenyl-l-ethanol-2-amine, prepared according to J. WEIJLARD et al., J. Am.
* - Trade-mark ~i :
Chem. Soc. 1951, 73, 1216, is added. The mixture is heated to dissolution. It is left to precipitate overnight and is filtered. 2.8 g of the salt (m.p. 175~C) are obtA i n~ . The mother liquors are kept.
The salt obtAin~ is taken up with water (20 ml), HCl (30 ml) and ether (100 ml). The mixture is stirred to dissolution. The organic phase is separated after settling has taken place, dried o and evaporated. Benzyloxycarbonylcyclopentyl-qlycine is ob~AineA, which is treated immediately with co.l~e.lLrated HCl (15 ml) and AcOH (15 ml).
The mixture is heated to reflux for 3 hours. It is evaporated to dryness. The residue is taken up with dry ether, filtered off and dried. (S)-Cyclopentylglycine hydrochloride is obtAine~.
t~]25 = + 10.4~ (c = 0.5, N HCl) m = 0.6 g.
The mother liquors are evaporated to dryness and the residue is taken up with H20 (50 ml), HCl (60 ml) and Et2O (300 ml). The mixture is st_rred and everything is dissolved. The ether phase is separated after settling has taken place, dried andevaporated. The benzyloxycarbonylcyclopentyl-glycine (4.3 g) is recovered and is placed in absolute ethanol (50 ml) with (+)-(lS,2R)-1,2-diphenyl-l-ethanol-2-amine (3.30 g). The mixture is heated to dissolution, left stAn~ overnight and filtered. 4.15 g of salt are obt~ine~.
M.p. 175~C
This salt is taken up with water (20 ml), N HCl (40 ml) and ether (200 ml). The mixture is stirred. The ether phase is dried and evapc-zted and the residue is then treated with concentrzted HCl (10 ml) and acetic acid (100 ml). The mixture is heated to reflux for 3 hours and concentrated under vacuum and the residue is taken up with anhydrous ether to obtain (R)-cyclopentylglycine h~dlochloride .
2166~03 m = 1.2 g [~]D5 = -10.5 (c - 0.85, N HCl) Optical purity of the (R)-cyclopen~ylglyc_3e:
0.10 g of the above hydrochloride are dissolved in absolute methanol. The mixture is cooled to -40~C, 0.5 ml of thionyl chloride is added and the mixture is left for 24 hours at room temperature. ~t is concentrated under vacuum, the residue is taken up in anhydrous chloroform o (20 ml), and triethylamine (0-2 ml) and (S)-phenylmethyl isocyanate (0.074 ml) are added.
The mixture i8 left for 24 hours and the chloroform is then evaporated off. The residue is chromatographed on silica gel; eluent: ethyl acetate. Conre~tration of the pure fractions yields 0.1 g of the methyl ester. The spectrum in CDC13 shows, at around 3.8 ppm, the presence of two signals for -CO2CH3. ~ntegr2t_0n shows that the weaker signal represents 4~, the more intense signal 96~.
The enantiomeric excess is hence 92%.
It is also possible to prepare the cycloal~yl-~-amino acids of R or S configuration by stereospec fic enzymatic hydrolysis of the correspo~ing racemic N-acetyl derivatives, according to J. HILL et al., J. Org. Chem., 1965, 1321.
(S)-2-{[1-Phenyl-5-(4-pyridyl)-3-pyrazolyl]carbonyl-amino}-4-methylpentanoic acid methyl ester.
(I): R=H; n=O; X~=H; X=_CH2_CH_(CH3)2; Z=OCH3; RI=C8H5;
~IV--n;
/~
RV = '~ N
/
O.35 g of 1-phenyl-5-(4-pyridyl)-3-pyrzzole_zr-boxylic acid is di~solved in 5 ml of dimethylfo~ ? ~n the presence of 0.45 ml of diisop~op~lethylamie (DTPEA) and 0.59 g of benzotriazolyl-N-oxytris(dimethy~amino)-~1~6~0~
-phosphonium hexafluorophosphate (BOP). 0.23 g (1 equi-valent) of (S)-leucine methyl ester hydrochlor.de, dissolved in 0.4 ml of DIPEA, is then added a..~ the reaction mixture i~ left overnight at room t~mrerature.
BenzyloxycArbonylcyclopentylglycine (5.54 g) i8 dis~olved in abQolute ethanol (65 ml).
(-)-(lR,2S,)-1,2-Diphenyl-l-ethanol-2-amine, prepared according to J. WEIJLARD et al., J. Am.
* - Trade-mark ~i :
Chem. Soc. 1951, 73, 1216, is added. The mixture is heated to dissolution. It is left to precipitate overnight and is filtered. 2.8 g of the salt (m.p. 175~C) are obtA i n~ . The mother liquors are kept.
The salt obtAin~ is taken up with water (20 ml), HCl (30 ml) and ether (100 ml). The mixture is stirred to dissolution. The organic phase is separated after settling has taken place, dried o and evaporated. Benzyloxycarbonylcyclopentyl-qlycine is ob~AineA, which is treated immediately with co.l~e.lLrated HCl (15 ml) and AcOH (15 ml).
The mixture is heated to reflux for 3 hours. It is evaporated to dryness. The residue is taken up with dry ether, filtered off and dried. (S)-Cyclopentylglycine hydrochloride is obtAine~.
t~]25 = + 10.4~ (c = 0.5, N HCl) m = 0.6 g.
The mother liquors are evaporated to dryness and the residue is taken up with H20 (50 ml), HCl (60 ml) and Et2O (300 ml). The mixture is st_rred and everything is dissolved. The ether phase is separated after settling has taken place, dried andevaporated. The benzyloxycarbonylcyclopentyl-glycine (4.3 g) is recovered and is placed in absolute ethanol (50 ml) with (+)-(lS,2R)-1,2-diphenyl-l-ethanol-2-amine (3.30 g). The mixture is heated to dissolution, left stAn~ overnight and filtered. 4.15 g of salt are obt~ine~.
M.p. 175~C
This salt is taken up with water (20 ml), N HCl (40 ml) and ether (200 ml). The mixture is stirred. The ether phase is dried and evapc-zted and the residue is then treated with concentrzted HCl (10 ml) and acetic acid (100 ml). The mixture is heated to reflux for 3 hours and concentrated under vacuum and the residue is taken up with anhydrous ether to obtain (R)-cyclopentylglycine h~dlochloride .
2166~03 m = 1.2 g [~]D5 = -10.5 (c - 0.85, N HCl) Optical purity of the (R)-cyclopen~ylglyc_3e:
0.10 g of the above hydrochloride are dissolved in absolute methanol. The mixture is cooled to -40~C, 0.5 ml of thionyl chloride is added and the mixture is left for 24 hours at room temperature. ~t is concentrated under vacuum, the residue is taken up in anhydrous chloroform o (20 ml), and triethylamine (0-2 ml) and (S)-phenylmethyl isocyanate (0.074 ml) are added.
The mixture i8 left for 24 hours and the chloroform is then evaporated off. The residue is chromatographed on silica gel; eluent: ethyl acetate. Conre~tration of the pure fractions yields 0.1 g of the methyl ester. The spectrum in CDC13 shows, at around 3.8 ppm, the presence of two signals for -CO2CH3. ~ntegr2t_0n shows that the weaker signal represents 4~, the more intense signal 96~.
The enantiomeric excess is hence 92%.
It is also possible to prepare the cycloal~yl-~-amino acids of R or S configuration by stereospec fic enzymatic hydrolysis of the correspo~ing racemic N-acetyl derivatives, according to J. HILL et al., J. Org. Chem., 1965, 1321.
(S)-2-{[1-Phenyl-5-(4-pyridyl)-3-pyrazolyl]carbonyl-amino}-4-methylpentanoic acid methyl ester.
(I): R=H; n=O; X~=H; X=_CH2_CH_(CH3)2; Z=OCH3; RI=C8H5;
~IV--n;
/~
RV = '~ N
/
O.35 g of 1-phenyl-5-(4-pyridyl)-3-pyrzzole_zr-boxylic acid is di~solved in 5 ml of dimethylfo~ ? ~n the presence of 0.45 ml of diisop~op~lethylamie (DTPEA) and 0.59 g of benzotriazolyl-N-oxytris(dimethy~amino)-~1~6~0~
-phosphonium hexafluorophosphate (BOP). 0.23 g (1 equi-valent) of (S)-leucine methyl ester hydrochlor.de, dissolved in 0.4 ml of DIPEA, is then added a..~ the reaction mixture i~ left overnight at room t~mrerature.
5 The solvents are concentrated under vacuum, the residual oil is extracted with dichloromethane and this solution is washed with water, then with sodium bicarbonate solution and again with water. The organic phase is dried over sodium sulphate and then concentrated under vacu~m.
The residue is chromatographed on silica gel; eluent~
ethyl acetate.
m = 0.18 g lH NMR spectrum of the compound 1: 3H at 8.82 (M, Har o to N and CONH); 5H at 7.50 lM, Phe Har); 3H at 7.2~
tHar m to N and pyrazole H4); lH at 4.60 (M, ~-Leu H); 3H
at 3.77 (S, CO2C~); lH at 2.00 (M, ~-Leu H); 2H at 1.70 (M, ~-Leu H); 6H at 1.00 (2D, Leu C~b).
(S)-2-{[1-Phenyl-5-(2-naphthyl)-3-pyrazolyl]-car~onylamino}-3-phenylpropanoic acid.
(I): R=H; n=0; X'=H; X=-CH2-C6Hs; Z=OH; RI=C6Hs; R~-H;
~VV, Preparationof5-(2-naphthyl)-1-phenyl-3-pyrazolecarbonyl chloride.
5 g of 5-(2-naphthyl)-1-phenyl-3-pyrazole-carboxylic acid are dissolved in 56 ml of toluene, and 3.5 ml of sulphinyl chloride are added dropwise to this solution. The mixture is heated to 90~ for 2 1/2 h, then concentrated under vacuum. The residual oil is taken up twice in toluene and concentrated under vacuum.
m = 5 g Preparation of the compound 2.
4.g g of (S)-phenylalanine are added to 60 m~ of 2N sodium hydroxide solution, and a solution of 4 g of the acid chloride prepared above, dissolved in 65 ml of tetrahydrofuran, is then added dropwise. The reaction mixture is left overnight at room temperature znd then concentrated under vacuum. The residue is taken up in water and the pH is ad~usted to 1 by A~ing hydrochloric ac~d. The solution i~ extracted with dichloromethane and the organic phase is washed with water and with saturated sodium chloride solution, dried over sodium sulphate, filtered and ronre~trated under vacuum. The residue is ~e~ ysLallised from pentane.
m = 2 g M.p. 226~C
o EXAMPLE 3 (S)-N,N-Diethyl-2-{tl-phenyl-5-(2-nArhthyl)-3-pyrazolyl~-carbonyl~TninQ}-3-phenylpropAn~
(I): RzH; n=0; X'=H; X=-c~2-c6Hs; Z=-N-(C2RS) 2;
F~=C6HS; R~=H;
RV = ~
2 g of the product obtAin~ according to Example 2, 0.88 g of dicyclohexylrArho~iimide (DCCI) and 1.14 g of l-hydroxybenzotriazole (HO8T) are dissolved in 68 ml of tetrahydrofuran and the mixture is stirred for 3/4 hour at room temperature. 0.4 g of diethyl~inp is then 20 added and the reaction mixture is left at room tPmrerature for 24 hours.
The dicyclohexylurea is separated by filtration and the mother liquors are concentrated under vacuum. The residue is chromatographed on silica gel; eluent: ethyl 25 acetate. The fractions of pure product are concentrated under vacuum and the residue is ~CSy~ Lallised from pentane.
m = 1.46 g M.p. 70~C
EXA~PLE 4 (S)-2-{(l-Phenyl-4,5-dihyd~oLe..z[g];n~A7ol-3-yl)c~rho~yl-amino}-4-methylpentanoic acid.
- 2161~903 1~
N - N
NH- CH -CH2-CH(CH3)~
O COOH
A) ~-Retocarbethoxy-~-tetralone sodium ~alt.
This intermediate is prepared according to the method described by D. P~M~SR et al. In~ An Journal of Chemistry, 1989, 28B, 76-78.
B) l-Phenyl-4,5-dihydrobenz[g]indazole-3-carboxylic acid ethyl ester.
8.04 g of the sodium salt obtAinP~ above are dissolved in 100 ml of acetic acid. 3.3 ml of phenyl-hydrazine are added and the reaction mixture is heated to reflux for 8 hours. The cooled mixture is poured into ice-cold water; a precipitate is separated by filtration and washed with water and then with pentane.
m = 10.5 g C) l-Phenyl-4,5-dihydrobenztg~indazole-3-c8rboxylic acid.
9.S g of the product obtAinP~ above are dissolved in 100 ml of methanol and 100 ml of water. 4.2 g of potassium hydroxide are added and the reaction mixture is heated to reflux for 5 hours. The mixture is poured into ice-cold water and the resulting mixture is then washed with ethyl acetate. The aqueous phase is acidified to pH 2 by ~ing hydro~hloric acid, and a precipita'e i8 separated by filtration and washed with water ar.d then with pentane.
m = 7.3 g D) l-Phenyl-4,5-dihydrobenz[g]indazole-3-carbonyl chloride.
2.8 g of the acid obt~ineA above are dissolved in 100 ml of toluene, 2.2 ml of sulphinyl chloride are then added and the mixture is heated to 100~C for 5 hours. The 6~03 solution is concentrated under vacuum, 20 ml of toluene are added and the mixture is concentrated under v2cu~m.
The same operation is repeated twice.
E) Compound 4 0.88 g of (S)-leucine is dissolved in a solution of 1.33 g of sodium hydroxide in 20 ml of water. This solution is cooled, 0.99 g of the acid chloride prepared above, dissolved in 16 ml of tetrahydrofuran, ~s then added and the reaction mixture is left stirring at room 0 temperature for 18 hours. The solution is concentrated under vaccum, and the residue is taken up in ice and acidified to pH 2 by A~ing hydrochloric acid and then extracted with ethyl acetate. The organic phase is dried over sodium sulphate, filtered and concentrated ur.der vacuum. The residue is ec~y~LAllised from iSG~ r o~yl ether.
m = 1 g N.p. 100~C
( S ) -2-{[1-Benzyl-3-(2-naphthyl)-5-pyrazolyl]carbonyl-amino}-3-phenylpropanoic acid.
RzH; n=0; X~=H; X=-cH2-c6Hs; Z=OH; R~a=~C~2~C6H5;
RIv=H; /C¢~
A) The reaction of methyl 2-naphthoyl~y~uvate with benzylhydrazine hydrochloride yields a mixture of the following esters: 1-benzyl-5-(2-naphthyl)-3-pyrszolecArhoxylic acid methyl ester and l-benzyl-3-(2-naphthyl)-5-pyrazolecarboxylic acid methyl ester.
Chromatography on silica gel enables the two isomers to be separated. l-Benzyl-5-(2-naphthyl)-3-pyrazolPrArho~ylic acid methyl ester is eluted first with a 50:50 (v/v) ethyl acetate/~eYAne mixture. 1-Benzyl-3-( 2-naphthyl)-5-pyrazolerArh~Yylic acid methyl este. is eluted as a second fraction.
B) 1-Benzyl-3-(2-naphthyl)-5-pyrazol~rArhoxylic acid.
216690~
The acid was prepared by saponification of the ester obtA i n~ above.
C) l-Benzyl-3-(2-naphthyl)-5-pyrazolecArhQnyl chloride.
The acid chloride i8 prepared by the action of sulphinyl chloride on the above acid, and is not isolated.
D) Compound 5.
0.28 g of (S)-phenylalanine are dissolved in a cooled sodium hydroxide solution. A ~olution of 0.3 g of the acid chloride prepared above in 5 ml of Th~ is then added and the reaction mixture is left at room temperature-for 24 hour~. The THF is concentrated under vacuum, and the residue is taken up in water and neutralised by A~ing concentrated ~y~lG~hloric acid. The product i~ extracted with ethyl acetate and the organic pha~e is dried over sodium sulphate and concentrated under vacuum. The residue is le~ y~Lallised from cycloht~YAn~ .
m = 1 g M.p. 100~C
(S)-2-{~1-(4'-~ethoxycinnamyl)-5-(4-pyridyl)-3-pyrazolyl]carbonylamino}-4-methylpentanoic acid methyl ester.
(I): R=H; n=0; X'=H; X=-CH2-CH-(CH3)2; Z = OCH3;
R~ = -CH2-CH~CH ~ OCH3 ; R~=H;
Rv = ~ N
A) 1-(4'-Methoxycinnamyl)-5-(4-pyridyl)-3-pyrazo'eczr-boxylic acid methyl ester.
4.6 g of 5-(4-pyridyl)-lH-pyrazole-3-carboxylic acid methyl ester are dissolved in 60 ml of dimethyl-formPmide, 0.63 g of sodium hydride in 80% suspension in oil is then added and the reaction mixture is heated to 40~C for 1 hour. A solution of 5.2 g of - ~66~03 4'-methoxycinnamyl bromide, dissolved in 60 ml of dimethylfor-mamide, is then added to the cooled mixture and the reaction mixture is left at room te~pera_~e cO
12 hours. The dimethylformamide is concentrated under vacuum, the residue is taken up in water and extracted with ethyl acetate and the organic phase is dried over _ sodium sulphate, filtered and concentrated under vacuum.
The residual oil is chromatographed on silica gel;
eluent: 50:50 (v/v) ethyl acetate/cycloh~Y~ne. The o fractions of pure product are concentrated under vacuum.
m = 2.6 g M.p. 118~C
B) Compound 6 0.4 g of the acid obtAi~e~ above is dissolved in 12 ml of dimethylformamide in the presence of 0.63 ml of DIPEA and O.53 g of BOP. O.22 g of (S)-leucine methyl ester hydrochloride, dissolved in 0.63 ml of DIPEA, is then added and the reaction mixture is left overnight at room temperature. The dimethylformamide is concentrated under vacuum and the residue is taken up in water. The product is extracted with ethyl acetate and the organic phase is dried over sodium sulphate, filtered and concentrated under vacuum. The residue is solidified in diisopropyl ether.
m = O.lS g M.p. 172-C
(S)-2-{3-tl-(4'-Nethoxycinnamyl)-5-(4-pyridyl)-3-pyrazolyl]carbonylamino}-3-phenylpropanoic acid sod:u~
salt.
(I): R=H; n=O; X~=H; X=_CH2_C~H5; Z=O Na~
RI = -CH2-CH=CH ~ OCH3 ; R~=H;
RV = ~N
~166 903 Using the procedure described in Example 6, and replacing (s)-leucine methyl ester hydrochloride by (S)-phenylAlAnin~ methyl ester hydrochloride, the ~e~hyl ester is obtAine~, which ester is hydrolysed to a sodium salt with 0.9 equivalent of sodium hydroxide in 10 ml of 96~ strength ethanol. The mixture is left overnight at room temperature and concentrated under vacuum and the residue is washed with ether. After filtration, the compound 7 i8 obt~ine~.
M.p. 137~C ~~
2-{[1-(5-Isoquinolyl)-5-(2,6-dimethoxyphenyl)-3-pyrazolyl]carbonylamino}-2-adamantanecarboxylic ac d.
(I): R--H ; n=0 ; x-f-X = ~
Z - OH ; RI= ¦ ~ ; RIV = H
RV = H3CO ~ OCH3 0.75 g of 2-amino-2-adamantanecar~oxylic ac d s dissolved in 20 ml of pyridine. 1.4 g of 1-(5-iso-quinolyl)-5-(2,6-dimethoxyphenyl)-3-pyrazolecarbonyl chloride, dissolved in 20 ml of dichloromethane, a~e added and the reaction mixture is left overnight at room temperature. It is concentrated under vacuum, the residue is taken up with pH 2 buffer, the mixture is st~rred and the precipitate i5 filtered off and rinsed with diisop o~yl ether.
m = 0.4 g M.p. > 260~C
2166gO3 2-{tl-(5-Quinolyl)-5-(2,6-dimethoxyphenyl)-3-pyrazolyl]-carbonylamino}-2-~A~ntanecarboxylic acid.
(I): R=H ; n=0 ; X-C-X'= ~
Z = OH ; RI = ¦ ~ ; R~V = H
RV = H3CO ~ OCH3 0.23 g of 2-amino-2-adamantA~rArhoYylic acid, O.5 g of 1-(5-quinolyl)-5-(2,6-dimethoxyphenyl)-3-pyrazol~rArhonyl chloride and 0.7 g of potass~um hydroxide are dissol~ed in 25 ml of dichloromethane i~
the presence of 0.1 g of Aliquat 336-.
o The reaction mixture is stirred overr.ight at _oom temperature, 0.7 g of potassium hydroxide is zdded znd the mixture is stirred for 4 hours. It is filtered and 0.2 g of the expected product is obtAin~.
M.p. ~ 260~C
(S)-2-{~1-(4-Chloro-l-naphthyl)-5-(2,6-dihydroxyphenyl)-3-pyrazolyl~rArho~ylamino}h~YAnoic acid.
(I): R=H ; n=0 ; X' = H ; X = (CH2)3-CH3 Z = O H : Rl= I ~ ; Rlv = H
RV = H O ~ OH
0.3 g of 2-{[1-(4-chloro-1-naphthyl)-5-(2,6-di-methoxyphenyl)-3-pyrazolyl]carbonylamino}h~YAno czcidis dissolved in 6.7 ml of dichloromethane and the mixtuse is cooled to -70~C. 5.7 ml of boron tribromide, dissolved in 20 ml of dichlormethane, are added dropwise and the reaction mixture is left for 2 hours at -70~C. It is allowed to return to room temperature, and 12 ml of water are then added while cooling. Concentrated NaOH is added to pH 14. The aqueous phase is washed with ether and o brought to pH 2, the product is extracted with ethyl acetate and the organic phase i8 dried over sodium sulphate, filtered and evaporated. The residue is crystallised from diiso~ u~yl ether.
m = 0.13 g M.p. > 260~C
2-{~1-(1-Naphthyl)-5-(2,6-dimethoxyphenyl)-3-pysazolyl~-carbonylamino}-2-adamantanecarboxylic acid.
R=H ; n = O ; X-C-X'= ~
Z = OH ; RI= I X ; RIV = H
RV = H3CO ~ OC~3 0.107 g of sodium hydroxide in 1.36 ml of wzter ~nd 0.51 ml of tetrahydrofuran are cooled to 0~C. 0.52 g of 2-2mino-2-adamantAn~cA~h~ylic scid is added n a single portion, and 0.53 g of 1-(1-naphthyl)-5-(2,6-di-methoxyphenyl)-3-pyrazolec~ho~yl chloride, dissolved ~n 3 ml of tetrahydrofuran, is then added dropwise. ~he mixture is left for 10 minutes, and the same _~our.t of the above acid chloride, in 3 ml of tetrahydrofuran, is added again; simultaneously, 1.32 ml of 2N sodi~m hy~roxide a_e added. The reaction mixture is left fo= 4 days at room temperature; successively, ice-cold water is added and concentrated hydrochloric acid is added to pH 1, and the precipitate is filtered off. The crystals are washed with diiso~pyl ether.
m = 0.48 g M.p. > 260~C
Methyl 2-{tl-(1-naphthyl)-5-(2,6-dimethoxyphenyl)-3-pyrazolyl]carbonylamino~-2-adamantanecarboxylate.
(I) : R=H ; n=0 ; X-C-X'= ~
Z = OCH3 ; RI = ¦ ~ ; RIV = ~ ;
RV = H3CO ~ OCH3 ~ ~' 0.5 g of the compound prepsred in Example 11 is dissolved in 34.6 ml of anhydrous tetrahydrofurzn znd 4 ml of dimethylformamide. 3.5 ml of water and 0.208 g of caesium cArho~Ate are added and the reaction mix~ure ~8 left at room temperature for 1 hour. It is ~on~entrated under vacuum and treated azeotropically with toluene. The residue is taken up in 5 ml of tetrahydrofuran. 0.6 m' of methyl iodide is added and the reaction mixture is left for 1 hour at room temperature. It is concentrated under ~acuum, the residue is taken up in water, the mixture s stirred and the precipitate i~ separated by filtration.
The precipitate is washed with water and with pentane.
m - 0.38 g N.p. 242-244~C
- ~166~Q3 2-{tl-(7-Chloro-4-quinolyl)-5-(2,6-dimethoxyphenyl)-3-pyrazolyl]csrbonylamino}-2-adamantAnecArboxylic acid.
(I) : R=H ; n=0 ; X-C-X'= ~
Z = OH : Rl~ I ~ ; RIV = ~ ;
RV = H3CO ~ OCH3 Using the procedure employed in Example 8, and replacing the acid chloride by l-(7-chloro-4-quinolyl)-5-(2,6-dimethoxyphenyl)-3-pyrazole~rhonyl chloride, the intermediate compound of formula:
,N ~~~~O
~' is obtAine~, the melting point of which is 249~C.
0.1 g of this intermediate is dissol~ed in 5 ml of dichlormethane; 5 ml of trifluoroacetic acid are added and the mixture is left for half an hour at room temperature. It is concentrated under vacuum to o~tain the expected compound.
m = 0.080 g '~166903 M.p. ~ 260~C
By repeating any one of the procedures desc_~bed in Examples 1 to 13, the compounds shown in Tables 1 to 15 below were prepared. In these tables, R3, when it is 5 used, .e~.~aents the groups X
- (CH2)n - C--C-- Z
X' O
21~903 .
CO
~ N' N
.
~1 F~r~ lC /R M.p.; C
n~ --N C~ . nn \R3 s;~lvent ~2~
15 - NH-CH2-CO2 Et 116 ~2~
16- NH-(CH2)2-C02 H - 17û
L~20 17C~3-(CH2)3- ,CH-C~2H S 7û
-NH CH
18(CH3)2-CH-fH-CO2H S 152 -NH ~2 19C6H5-CH2- 1C~-C~2H S 214 -NH ~2 20C6H5-(CH2)2- 1CH-CO2H S 79 -NH CH
-NH ~2 22NH2-(CH2)4- ,CH-CO2H S 150 -NH ~2~ (HCl) 21~ 9 0 i~
~C-NH-(CH2)3-fH-CO2H S 125 H2N -NH CH (HCl) 24HO2C (CH2)2-fH-co2H S ~020 25,~N~Co2H S '12 iPr, O
~ ~ CH2--CH--C02H
26 r ~ s 207 NH L~20 H
CHr CH--C02CH3 ~ \ H iPrOH
28 N ~ - NH S EtOH,H2O
29 ~ RS 84 ~ Pn,~t20 H~ C O2H
~N--CN--CN 4~\
Example R~ R~ R5 R~5 R"5 z "~ P-; ~C
crystal.
solvent EtO~
31 H H 4 No2 H H OCH3 69 Hx iPr20 33 H H 2-C1 4-Cl H O~ 108 iP~2O
34 H H 2-CH3 4~CH3 6-C~3 OH 120 iPr20 3~ H H 2-OCH3 6-OCH3 H O~I 99 iPr2O
36 1 F H 2-P H H ou 203 ~2~
37 4-P H ~Cl H H OH 90 Pn ~2~
i~2o 40, 4-Cl H 4-CI H H OE~ 98 Pn ~16~90~
41 ~ CH3 H 4-OCH3 H H OH 94 i~2o 42 4~3 H 4-Cl H H OH 84 P~
iPr20 44 2-C1 4-Cl 4-Cl H H OH 110 Pn 4S 2-Cl S-Cl 4-CH3 H H OH 90 Pn 46 2-CH3 5-F 2-Cl H H OH 100 Pn 47 3-a 4 Cl H H H OH 83 -48 3-C1 4-Cl 4 CH3 H H OH 100 Pn 49 4-t-Bu H H H H OH 88 C~
Hx S1 4-NH2 H H H H ~C~3 9~
Hx 52 ~NH2 H H H H ONa 155 he compound~ of Table 2 are all of S configuration.
- ~166~03 C--N--CH--C~2 ~R6 ,N
&le ~ R,~' R Z R6t2~1~1.yl C* M.p; ~
solven~
53 H H H OH H 1 S 2"1 ~2 54 H H H OH H 2 R ' '4 ~2 E~
56 H H H OH C:l 1 R.S 212 ~2 57 H H H OH C:l 2 R S 196 ~2 E~
Pn 2-C1 5-Cl H OH H 1 S 115 61 2~ 5-Cl H OH H 2 S lOS
Hx 62 2-C1 5n H OH Cl 1 R S 1;9 Hx 63 2-a 5-Cl H OH a 2 R S '~'1 iPr70 ~1669()~
o4 3-a ~a H OH H 1 S ~_1 3-a 4 Cl H ONa H 2 S 140 ~tOH
TaBL~ 4 ~ ~ /C~3 C--N--CH--CH2--c~
RV~ ~N coz \ CH3 N
~ple M.p.; ~C
Z RV C~crys~l.
solvent 66 H H OH ~ S 86 67 H H OH ~ S 107 oc~3 68 H H OH ~._OCH3 oc~3 69 H H OH ~t S 16S
\~ ~ (Ha ~ 2166903 ~F H OH _~ S 174 71 1 F H OH ~t--a S 92 72 l F H OH ~ S 96 73 ~Cl H OH {~--a S 89 74 4-t-Bu H OH ~ S 88 2-Cl S~ OH ~C~3 i 2~25O
76 3-Cl 4 Cl OH ~ S 72 77 3 Cl 4 Cl OH {~C~3 98 78 3~ 4 Cl OH --~CH3 Pn 79 3-Cl ~Cl OH ~ S 135 2-C1 5 Cl OH ~ S 2_5 21~6903 T~BLE 5 C-N-C~-COOH
~J~N~N C~3 C~3 R~
r.~."~.l, ~ R'~, Rv M.p.; ~C
CryStA~ At i 1~1 solver,.
oc~3 81 H H ~ 161 OCH~ O
rcH3 82 H H ~ 01 H3coJ~oc~3 AcOE~
~ ~,o 84 ~F H ~3 59 1 Cl H _~} 100 86 4-t-Bu H ~ 88 bJ' Y~x 87 3-C1 4-C1 ~ 83 ~ Y.7c 88 3-C1 1 Cl ~ 90 The compounds of Examples 81 to 88 are of S
conf iguration .
~fi, - ~-R3 ~1 ~
EKalple ~d~l~yl ~ 2; ~C
No R3 RS E~i~inn C~ crystal.
solvent 89 XO-CH2-fH-CO2H H 2 S '70 ~ AcOEt (cH3)2-cH-c~2-cH CO2H H 1 S 88 91 ~c~3 ~ 1 S ~06 CH3--CH2--CH--f~C02H L~20 92 CH3-(CH2)2- ,CH-C02H H 1 S 198 ~~
93 CH3 (CH2)3-CIH CO2H H l RS 92 CH
94 C~3 (CH2)3 ~c~i CO2H H 1 R 190 L~20 --~;H-C02H
,~ H 1 R S 2~6 L~ iPr~O
96 (CH3)3 C-fX-C02H E~ 1 S '30 iP~20 97 C~3 ~CH2)2 ,C~I-CO2H 6-OCH3 2 S 92 98 CH3-(CX2)3-C~H C~2H 6-OCH3 2 S 98 CH
99 (cH3)2-cH-f H-C~2H 6-OCH3 2 S 95 100 (CH3)2 CH CH2 ~CH C~2H 6-OCH3 2 S 95 Hx 101 (CH3)2-CH-CH2 CH-CO2H H 2 S 100 102 C6HS-(CH2)2- ,CH-C02H H 2 S 120 103 C6HS-CH2 cH-co2H 6-OCH3 2 S 95 Hx HN~
104 ~C NH-(C~2)3 fH CO H H 2 S 175 H N AcOEt H N~
105 C~NH-(CH~)3- ~CH'C02C~3 H 2 S 110 H N
~C~2 C~ CO~H
106 ~I H 2 S 200 AcOEt 107 ~ IH cH2-s-cH2-l H H 2 S 217 C02Na COCH3 EtOH
- ICH-CH2-CH2~ H 1 S 100 ~166903 R5~ 1~ COON R6 R~
FY~Fle M.p.; C
n~ R4 R6 RIv RS C* solver.~ ~
109 H Cl a Cl R S 1''~
Elx 110 F ~ a ~ s llo Hx 111 F Cl a . c! R S 100 Hx 4~
co~R ~co~/R
)~ ~N )~ ~N\
RI Ia E~ca~le ~R3 ~-P~; ~C
No RI RIa -N\ RVC* ~y ~dl R solvent ~H2_ C6~S-Cl ~-C~2~ ~
1l2 ~ --NH F S 158 ~2 ~ I ~ ¦
3 ~I C6H5~CH'~IC~~¦ S 130 ~I CO~ ~ L~20 4 ~D (C113)2-CN2 Cli-C~2~ ~ 5 80 ~H2_ --2--CH-CO H ~
1l5 ~I b ~ R S 120 C~2H 4~ ~c 117 ~ 2 -N- ICH-(cH2)3-cH3 ~ S 69 21~6 903 H oc~3 118 !3 C02H O~oc~ 1J0 9 ~cl -N-f~O ccYl CH
120 ~ f~ ocY~
121 fH2 f -a ~oc~3 109 -122 ~D HN-fH~ ~ocY~
216690s~
TAB~E 9 ,b b,D
Fy~A~ltrle M.p.; C
n~ -R3C* Crys~A~
solvent 123 (CH3)2-CH-CI H-C~2H S 200 ~-~2~
124 C6HS-cH2-fH-co2H S 110 ~0 o R
C-l-R3 FY,A-r~rle R M.p.; ~C
n~ I crys~lli~
-N-R3 solu~nt 125 C6HS-ClH-c02H 115 NH-- Pn 126 (CH3)2-C~-fH-C02H 110 NH-- ~,~
' 21~6~03 127C~3-(CH2)2-C~-COoH 90 NH- P~
128(C~3)2-c~-cH2-fx-co2H 100 NH- Hx 129CH3-(CH2)3-CH-CO2H
NH- Ph 130C6HS-cH2-lcH-co2~ lC0 NH- Pn The compounds 125 to 130 are of S configuration.
~ IR
R. ~ R~
Ex n~ ~ ~ RS R~5 R"s C* c~al.
-N-~3 solvent 131(cH3)2-cH-~cH-co2H H H H H S 1;0 NH-- ~c 132CH3-(CH2)3-lCH-cO2H H H H H S 100 NH- Pn 133(cH3)2-cH-cH2-~CH-cO2H H H H H S 2~0 ~H- Pn 134C6H5 - CH~- ~CH-C02H H H H H S 110 NH-135cH3-(cH.)3-~cH-co2H H 24cH3 6~C~3 H S 113 NH-21669~3 .
136 l H 24CH3 6~CH3 H S250 ~ Pn 137 l H 2~CH3 6-OCH3 H ~S136 ~ Pn -N-fH~ H 2~XC~3 6-OCH3 H S ~2 139 N~ H 24CH3 6~CH3 H 122 140 1 A >260 -N~ H 24CH3 6-OCH3 H Hx 141 ~ D--~ 112 -~-fH-cH2 ~ H 24CH3 6-OCH3 H SL~2 -N-lcH-(CH2)3-C~2H H 2~CH3 6~CH3 H S ~2 CO,H
143~ fH3 116 -N-f ~ H 2 4CH3 6-OCH3 H RS ~2 144 -N~ H 24CH3 6-OCH3 H - >260 CO2H Hx 145 H A >260 -N ~ CH3 H 2-OCH3 64CH3 H . Hx 146 1 r--\ >260 -N~H V H 24CH3 6-OCH3 H ~S Hx 147 ~ ~ ~260 -N- ICH~ H 2~CH3 6-OCH3 H S Hx ~1~690353 L~ iPr2O
149 -Nbco2H H 24CH3 4-OCH3 '10 150 ~N CH~) H 24CH3 54CH3 H 2''3 lSl ~ fH--O H 2-OCH3 4 OCH3 H S iPr1O
H
152 -N--lH-CO2H H 24CH3 64CH3 H R 2¢7 o -N 7~1 H 24CH3 6-OCH3 H Y.x 154 co~O H 2~CH3 6~CH3 132 155 IH ~ 114 -N7~,/ H 2-OCH3 6-OCH3 H Hx CO,,H
-N-ICH-c-(cH3)3 H 2-OCH3 6-OCH3 H S h~2o 157 H ~ CH3 244 -N-IC--CH H 2-OCH3 64CH3 H . iPr~O
CO.,H
158 EjI 106 _N_~H-(CH2)S-cH3 H 2~CH3 6~C~I3 H R S Hx 159 IH ~ H H S >260 -N~HV 24CH3 6-OCH3 H~x 21fi6gO3 160 1 >'60 --N-CH--O H2-OCH3 6-OCH3 H R Hx 161IH ~ . 174 -N7~ H2)11 H2-OC~3 6-OCH3 H H7c 162H A >260 -N ~ H2-OCH3 6-OCH3 H R SEtOH
163 ~ H2-OCH3 6-OCH3 H 24~
-~- ,C~
164-N-~;H--O H2-oc2H5 6~C2H5 H 2'_ 165-~7CN CH2~ 2-OCH3 6-OCH3 Et~O
CO.H
-X7~,D 2-OCH3 6~CH3 CH ~a 167-X 7CN-H H2~CH3 6-OCH3 H Et ~O
CO2H . HCI
168 -N~l H2-oc2H5 6-OC2H5 H iPr2O
~H3 169 ~ 3 H 2-OCH3 6-OCH3 H - >_60 21~6903 .
170 ~ >260 -N7~J H 2~CH3 6-OC~3 H R S C~,a, CO.,H -E~20 171,~ C7 >260 -N~ H 2-OCH3 64CH3 H iPr2O
172 /~ 120 -N~_J H 24CH3 64CH3 H S Pn 173-N-C~H--a H 2-OCH3 64CH3 H R S 81 ct~2CH3 Pn 174 ~ r ~260 -N- ~CH- ~_ H 24CH3 64CH3 H R SiPr~O.
175fH3 ,~ ., -N-ICH--~J H 24CH3 6-OCH3 ~ R S Hx CO,2H
176 ,~ ~50 )~ J~J, H 2~CH3 6-OC~3 H R S L~2O
H02C ~ -177 ~ H 2~CH3 6-OCH3 H R S L~2O
178~ C02H H 24CH3 44CH3 6-OCH3 R S 2'~9 ~1 L~20 179 ~ ~ H S ~260 ~ 24CH3 44CH3 6-OCH3 ~2~
180 --N~-cO2H 4-C1 24CH3 64CH3 H RS 125 L~ Hx 181 ~ 120 N fH (CH2)3~H3 4 Cl 24CH3 64CH3 H S Hx '~1669~3 82 /~ l~O
-N~,~ 4 Cl24CH3 64CH3 H S CH
183 H ~ H 2-CH3 6-CH3 H '80 - Et20 184 -N-C H 2~CH3 64CH3 H ~
185 Y H '06 -~-CH2~~2H 2~CH3 64CH3 H - L~2O
186 -N~ 4-C1 24CH3 6~CH3 H - >260 iPr~O
~ ~ 180 187 -N 7~ ~ H 24CH3 6-OCH3 H - McoH
C02H -H ~O
s~ , ~260 HN~J H 2~CH3 6~CH3 H R S Et~O
coo~3 R ~
189 -N-fH-CH2-O H 24CH3 64CH3 H S CH
NH- H 2~CH3 64CH3 H R S CH
21~5903 R'~R3 Ex. ~ C* M.p; ~C
n~ R~ R',~ R'~ -N-R3 R5 R'5 R~5 crystAl, solvent f~2~ 79 191 H H HCH3-(CH2)3-CH 3-OCH3 4~ 3 H S Y.x NH-f~2~ 69 192 H H HCH3-(CH2)3-CH 3 OCH3 4~CH3 ~-~C~3 S Y,x NH-f~2~ 90 193 H CH3-(CH2?3-~C~H2~C~3 4~CH3 6 OCH3 NH--194 H H CH2-NH- 3 3 H R S ~x f~2~ 9~
1953~C1 4~ HCH3-(CH2)3-CH 2-OCH3 6 OCH3 H S Y,x NH-196 3 Cl 4-Cl HQ~H_CO2H 2~CH3 ~OCH3 H R S 100 NH--i 2166903 197 2-C1 6-Cl H CH3-(cH2)3 cH 2~3 NH-f~2}
1982-C1 5-Cl H CH3-(CH2)3-C 2 0CH3 6-OCH3 H S Pn ~;O2H 85 199 3-C1 4-Cl H c6H~(cH2)2-cH-NH- H H H S C~
f~2~ 78 200 3 a 4~ H CH3-(CH2)3-~CH H H H S Y,x NH-201 3-C1 4-Cl H ~L ICH-CO2H H H H R S Hx NH-202 4 H H CH3_(CH2)3$H H H H S Yx t-Bu NH-(CH3)2-CH-cH2 66 203 H H H H2N-,C,-¢H H H H S Yx o NH-204 3-Cl 4 Cl H CH3-(CH2)3-CI; 2 OCH3 6~CH3 H S y~O
NaOOC
f~2~ 98 20S 3-C1 4-Cl H CH3-(CH2)3-CH 2 OCH3 4~ 3 6 OCH3 S CH
NH-2 0 6 2-Cl S-Cl H -N-fH-(cH2)3-cH3 2-OCH3 6-OCEI3 H S 64 C02C~{3 '~i669n~
'07 2-C1 3-Cl ~Cl -~- CH-CO-~ 2~CH3 6~ 3 H R,S cu b 208 2-C1 3-C1 4-C~N I H (CH2)3 CH3 2 OCH3~OCH3 H Pn 209 2-Cl 4 Cl 6-Cl-N-ICH-(C82)3-CH3 2~ 3 6 OC~ H Pn CO,H
210 2-Cl 4 Cl 6-Cl--N--ICH-CO2H 24CH3 6~3 H R S CH
}~ 79 211 3-CF3 5 CF3 HN ICH (CH2)3 CH3 2~H3 6~3 H Pn 212 3-CF3 5-CF3 H _N~;-co2H 2~CEI36~ 3 H R S
H
213 2-C1 3-Cl H_,~_ IC8-CO2H 2~C~I36 OC~3 H R~S HX
2~4 2-Cl 3~1 HN ~ H-(CB2)3 CH3 2~CH36 OCEI3 H Pn 215 2-C1 5-Cl H ~}~ 4-N02 H ~
216 2-C1 3-Cl H -N~ 2-OCH3 6-OCH3 H Hx 217 3 CF3 S~:3 H -N~ 2~ I3 6-0CH3 H S Hx C~2H
218 3-CF3 5 CF3 -N-CH2-co2H 2-0CH36~C~13 C~I
/~ 110 219 2-Cl 4 Cl 6-Cl --N~ 2~C~I3 6-OCH3 ~ H.x ~o 3-C1 4-Cl H -N-f Cli 2-C1 6-Cl H 240 ~l 3-Cl 4Cl HN CIH (CH2)3 CH3 2-C1 6-Cl H S 98 ~2 3-Cl '1 a H ~ f~9 2-C:1 6~ 0 ~3 3-Cl ~Cl H --Nb-CO2H 2-C1 6-Cl H ~ S p 224 2-a 4-a H --Nb-CO2N 2~3 6 OCH3 H R S ~, 225 2-Cl ~1 Cl HN-CIH-<CH2)3-CH3 2-OCH3 6-OCH3 H S 196 CO.H
226 3-CI 4-F H -N--CN-CO2N 20C~13 64~}3 H RS CH
227 3-Cl 4-Cl H --Nb-CO.H 2-F 6-F H R S L~r~O
228 3-Cl 4 Cl HN Cl H-(CH-)3 CH3 2-F 6-F H S Hx ~g 2-a s-a CO2N -~ 2-OC~I3 6~I3 H S 86 230 2-C1 6-Cl H -N-CH-CH2--0 2~OC~3 6~13 H S 268 ~166903 231 H H H -N-CH-(CH.)3-CH3 24CH3 4-OCH3 H Hx CO,H
232 H C~2H ~ 4-NO2 H H S 100 233 ~Cl H H --N--CH-Co2H 24CH3 6~I3 H R S 116 b ~ 169 234 4 Cl H HN cl H (CH2)3 CH3 24CH3 64C H3 H Hx 23S 2-Cl H H-N--lH-C02H 24C~3 H H R S
236 2~1 H HN ICH ~CH2)3 CH3 2~3 H H S
- 237 3 Cl 4-a H-N lH-C02H 24CH3 H Hx C~ ' ~ 85 238 3 Cl 4 a H~ CIH (CH~)3 CH3 24C~3 H H S Pn /___ 107 239 2-C1 5-Cl H -N~ 24CH3 6~ 3 H S Hx 240 3 Cl H -N-CH-~CH2)3-CH3 24C~I3 64CH3 S 96 CO.H
241 3-Cl H H--N--CH-CO.H 24CH3 64CH3 H R S C~
b ~ 83 242 3-Cl H H -N-cl H-(CU2)3-CH3 2-0CH3 64CH3 H S C~
~166903 243 3-C1 1 Cl H - N--CH-C02H 2 CH3 Y H R,S y b 244 3-Cl 4 Cl HN Cl H ~CH2)3-cH3 2~3 H H S 8S
245 3-C1 5-Cl H --N--CH-CO2H 2~CEI36 0C~3 H R S Yx 246 3-C1 5-Cl H N~ H (C~2)3 C~3 2~3 C~.3 H S PT~
247 H H H N~ H (CH2)3 C~3 2 OCH3 6~3 H S Pn ~ABLE 13 C--N--~.3 R'S R(I) Ex. R~ R'~ R~ IR C~~,~l;i~i~
-N-R3 solvent 248 2~C1;3 6~3 ~ ~ -a R 5 107 N C~2C~3 249 24CH3 6~3 ~ --Nbco ,H ~320 250 2W13 6~3 ~ -N-f~g~ R S ~' 1 251 2 0CH3 6 0CH3 ~5~ --Nbco2H R S L~l2o 252 2~0CH3 60CH3 1~ -~-fCH~O l17 253 2~H3 6~3 ~ -~N-f ~0 s L~20 2S4 2-oCH3 6~)CH3 b(~ -N~ L~020 co2~
255 2~C~3 6~0CH3 b~ f~ ~O S L~O
256 2 oCH3 6~3 ~ Co2H R S 118 /~ 128 257 2~CH3 64C~3 0 --N~_~ S P;l ~ -N-cH-(cH2)3-c~
258 24C~3 ~XH3 ~ C02H S Pn 259 24C~3 6~3 ~0 -~-fcHo~~ ~260 260 24C~3 6~0CH3 ~o H~ - L~r20 261 2 OCH3 6~3 ~NN -N~ L~_O
co2 262 2~3 64~I3~ ,S -N~l 26 CO~I
~ C--N--R3 H3C ~ N
i~N
~1 FY~ e . M.p.; ~, n~ R3 C~CrYSt~ At;~
solvent 263 C5HS_CH2_ ICH_C~2H S 105 264 C5HS_CH2 CI H_C~2CH3 S 80 2166~03 o R
OCH3 ll--N--R3 N~ lf OC}~3~
~nplc ~R M.p.; ~C
n~ -N C~ cryst~ tiOn R3 solvent H, I10 255 -N-cH-(cH2)3-cH3 S iPr O
H 1'0 266 --N--lCH-C~2H R S L~.'~O
267 ~ N~_ S CH
The residue is chromatographed on silica gel; eluent~
ethyl acetate.
m = 0.18 g lH NMR spectrum of the compound 1: 3H at 8.82 (M, Har o to N and CONH); 5H at 7.50 lM, Phe Har); 3H at 7.2~
tHar m to N and pyrazole H4); lH at 4.60 (M, ~-Leu H); 3H
at 3.77 (S, CO2C~); lH at 2.00 (M, ~-Leu H); 2H at 1.70 (M, ~-Leu H); 6H at 1.00 (2D, Leu C~b).
(S)-2-{[1-Phenyl-5-(2-naphthyl)-3-pyrazolyl]-car~onylamino}-3-phenylpropanoic acid.
(I): R=H; n=0; X'=H; X=-CH2-C6Hs; Z=OH; RI=C6Hs; R~-H;
~VV, Preparationof5-(2-naphthyl)-1-phenyl-3-pyrazolecarbonyl chloride.
5 g of 5-(2-naphthyl)-1-phenyl-3-pyrazole-carboxylic acid are dissolved in 56 ml of toluene, and 3.5 ml of sulphinyl chloride are added dropwise to this solution. The mixture is heated to 90~ for 2 1/2 h, then concentrated under vacuum. The residual oil is taken up twice in toluene and concentrated under vacuum.
m = 5 g Preparation of the compound 2.
4.g g of (S)-phenylalanine are added to 60 m~ of 2N sodium hydroxide solution, and a solution of 4 g of the acid chloride prepared above, dissolved in 65 ml of tetrahydrofuran, is then added dropwise. The reaction mixture is left overnight at room temperature znd then concentrated under vacuum. The residue is taken up in water and the pH is ad~usted to 1 by A~ing hydrochloric ac~d. The solution i~ extracted with dichloromethane and the organic phase is washed with water and with saturated sodium chloride solution, dried over sodium sulphate, filtered and ronre~trated under vacuum. The residue is ~e~ ysLallised from pentane.
m = 2 g M.p. 226~C
o EXAMPLE 3 (S)-N,N-Diethyl-2-{tl-phenyl-5-(2-nArhthyl)-3-pyrazolyl~-carbonyl~TninQ}-3-phenylpropAn~
(I): RzH; n=0; X'=H; X=-c~2-c6Hs; Z=-N-(C2RS) 2;
F~=C6HS; R~=H;
RV = ~
2 g of the product obtAin~ according to Example 2, 0.88 g of dicyclohexylrArho~iimide (DCCI) and 1.14 g of l-hydroxybenzotriazole (HO8T) are dissolved in 68 ml of tetrahydrofuran and the mixture is stirred for 3/4 hour at room temperature. 0.4 g of diethyl~inp is then 20 added and the reaction mixture is left at room tPmrerature for 24 hours.
The dicyclohexylurea is separated by filtration and the mother liquors are concentrated under vacuum. The residue is chromatographed on silica gel; eluent: ethyl 25 acetate. The fractions of pure product are concentrated under vacuum and the residue is ~CSy~ Lallised from pentane.
m = 1.46 g M.p. 70~C
EXA~PLE 4 (S)-2-{(l-Phenyl-4,5-dihyd~oLe..z[g];n~A7ol-3-yl)c~rho~yl-amino}-4-methylpentanoic acid.
- 2161~903 1~
N - N
NH- CH -CH2-CH(CH3)~
O COOH
A) ~-Retocarbethoxy-~-tetralone sodium ~alt.
This intermediate is prepared according to the method described by D. P~M~SR et al. In~ An Journal of Chemistry, 1989, 28B, 76-78.
B) l-Phenyl-4,5-dihydrobenz[g]indazole-3-carboxylic acid ethyl ester.
8.04 g of the sodium salt obtAinP~ above are dissolved in 100 ml of acetic acid. 3.3 ml of phenyl-hydrazine are added and the reaction mixture is heated to reflux for 8 hours. The cooled mixture is poured into ice-cold water; a precipitate is separated by filtration and washed with water and then with pentane.
m = 10.5 g C) l-Phenyl-4,5-dihydrobenztg~indazole-3-c8rboxylic acid.
9.S g of the product obtAinP~ above are dissolved in 100 ml of methanol and 100 ml of water. 4.2 g of potassium hydroxide are added and the reaction mixture is heated to reflux for 5 hours. The mixture is poured into ice-cold water and the resulting mixture is then washed with ethyl acetate. The aqueous phase is acidified to pH 2 by ~ing hydro~hloric acid, and a precipita'e i8 separated by filtration and washed with water ar.d then with pentane.
m = 7.3 g D) l-Phenyl-4,5-dihydrobenz[g]indazole-3-carbonyl chloride.
2.8 g of the acid obt~ineA above are dissolved in 100 ml of toluene, 2.2 ml of sulphinyl chloride are then added and the mixture is heated to 100~C for 5 hours. The 6~03 solution is concentrated under vacuum, 20 ml of toluene are added and the mixture is concentrated under v2cu~m.
The same operation is repeated twice.
E) Compound 4 0.88 g of (S)-leucine is dissolved in a solution of 1.33 g of sodium hydroxide in 20 ml of water. This solution is cooled, 0.99 g of the acid chloride prepared above, dissolved in 16 ml of tetrahydrofuran, ~s then added and the reaction mixture is left stirring at room 0 temperature for 18 hours. The solution is concentrated under vaccum, and the residue is taken up in ice and acidified to pH 2 by A~ing hydrochloric acid and then extracted with ethyl acetate. The organic phase is dried over sodium sulphate, filtered and concentrated ur.der vacuum. The residue is ec~y~LAllised from iSG~ r o~yl ether.
m = 1 g N.p. 100~C
( S ) -2-{[1-Benzyl-3-(2-naphthyl)-5-pyrazolyl]carbonyl-amino}-3-phenylpropanoic acid.
RzH; n=0; X~=H; X=-cH2-c6Hs; Z=OH; R~a=~C~2~C6H5;
RIv=H; /C¢~
A) The reaction of methyl 2-naphthoyl~y~uvate with benzylhydrazine hydrochloride yields a mixture of the following esters: 1-benzyl-5-(2-naphthyl)-3-pyrszolecArhoxylic acid methyl ester and l-benzyl-3-(2-naphthyl)-5-pyrazolecarboxylic acid methyl ester.
Chromatography on silica gel enables the two isomers to be separated. l-Benzyl-5-(2-naphthyl)-3-pyrazolPrArho~ylic acid methyl ester is eluted first with a 50:50 (v/v) ethyl acetate/~eYAne mixture. 1-Benzyl-3-( 2-naphthyl)-5-pyrazolerArh~Yylic acid methyl este. is eluted as a second fraction.
B) 1-Benzyl-3-(2-naphthyl)-5-pyrazol~rArhoxylic acid.
216690~
The acid was prepared by saponification of the ester obtA i n~ above.
C) l-Benzyl-3-(2-naphthyl)-5-pyrazolecArhQnyl chloride.
The acid chloride i8 prepared by the action of sulphinyl chloride on the above acid, and is not isolated.
D) Compound 5.
0.28 g of (S)-phenylalanine are dissolved in a cooled sodium hydroxide solution. A ~olution of 0.3 g of the acid chloride prepared above in 5 ml of Th~ is then added and the reaction mixture is left at room temperature-for 24 hour~. The THF is concentrated under vacuum, and the residue is taken up in water and neutralised by A~ing concentrated ~y~lG~hloric acid. The product i~ extracted with ethyl acetate and the organic pha~e is dried over sodium sulphate and concentrated under vacuum. The residue is le~ y~Lallised from cycloht~YAn~ .
m = 1 g M.p. 100~C
(S)-2-{~1-(4'-~ethoxycinnamyl)-5-(4-pyridyl)-3-pyrazolyl]carbonylamino}-4-methylpentanoic acid methyl ester.
(I): R=H; n=0; X'=H; X=-CH2-CH-(CH3)2; Z = OCH3;
R~ = -CH2-CH~CH ~ OCH3 ; R~=H;
Rv = ~ N
A) 1-(4'-Methoxycinnamyl)-5-(4-pyridyl)-3-pyrazo'eczr-boxylic acid methyl ester.
4.6 g of 5-(4-pyridyl)-lH-pyrazole-3-carboxylic acid methyl ester are dissolved in 60 ml of dimethyl-formPmide, 0.63 g of sodium hydride in 80% suspension in oil is then added and the reaction mixture is heated to 40~C for 1 hour. A solution of 5.2 g of - ~66~03 4'-methoxycinnamyl bromide, dissolved in 60 ml of dimethylfor-mamide, is then added to the cooled mixture and the reaction mixture is left at room te~pera_~e cO
12 hours. The dimethylformamide is concentrated under vacuum, the residue is taken up in water and extracted with ethyl acetate and the organic phase is dried over _ sodium sulphate, filtered and concentrated under vacuum.
The residual oil is chromatographed on silica gel;
eluent: 50:50 (v/v) ethyl acetate/cycloh~Y~ne. The o fractions of pure product are concentrated under vacuum.
m = 2.6 g M.p. 118~C
B) Compound 6 0.4 g of the acid obtAi~e~ above is dissolved in 12 ml of dimethylformamide in the presence of 0.63 ml of DIPEA and O.53 g of BOP. O.22 g of (S)-leucine methyl ester hydrochloride, dissolved in 0.63 ml of DIPEA, is then added and the reaction mixture is left overnight at room temperature. The dimethylformamide is concentrated under vacuum and the residue is taken up in water. The product is extracted with ethyl acetate and the organic phase is dried over sodium sulphate, filtered and concentrated under vacuum. The residue is solidified in diisopropyl ether.
m = O.lS g M.p. 172-C
(S)-2-{3-tl-(4'-Nethoxycinnamyl)-5-(4-pyridyl)-3-pyrazolyl]carbonylamino}-3-phenylpropanoic acid sod:u~
salt.
(I): R=H; n=O; X~=H; X=_CH2_C~H5; Z=O Na~
RI = -CH2-CH=CH ~ OCH3 ; R~=H;
RV = ~N
~166 903 Using the procedure described in Example 6, and replacing (s)-leucine methyl ester hydrochloride by (S)-phenylAlAnin~ methyl ester hydrochloride, the ~e~hyl ester is obtAine~, which ester is hydrolysed to a sodium salt with 0.9 equivalent of sodium hydroxide in 10 ml of 96~ strength ethanol. The mixture is left overnight at room temperature and concentrated under vacuum and the residue is washed with ether. After filtration, the compound 7 i8 obt~ine~.
M.p. 137~C ~~
2-{[1-(5-Isoquinolyl)-5-(2,6-dimethoxyphenyl)-3-pyrazolyl]carbonylamino}-2-adamantanecarboxylic ac d.
(I): R--H ; n=0 ; x-f-X = ~
Z - OH ; RI= ¦ ~ ; RIV = H
RV = H3CO ~ OCH3 0.75 g of 2-amino-2-adamantanecar~oxylic ac d s dissolved in 20 ml of pyridine. 1.4 g of 1-(5-iso-quinolyl)-5-(2,6-dimethoxyphenyl)-3-pyrazolecarbonyl chloride, dissolved in 20 ml of dichloromethane, a~e added and the reaction mixture is left overnight at room temperature. It is concentrated under vacuum, the residue is taken up with pH 2 buffer, the mixture is st~rred and the precipitate i5 filtered off and rinsed with diisop o~yl ether.
m = 0.4 g M.p. > 260~C
2166gO3 2-{tl-(5-Quinolyl)-5-(2,6-dimethoxyphenyl)-3-pyrazolyl]-carbonylamino}-2-~A~ntanecarboxylic acid.
(I): R=H ; n=0 ; X-C-X'= ~
Z = OH ; RI = ¦ ~ ; R~V = H
RV = H3CO ~ OCH3 0.23 g of 2-amino-2-adamantA~rArhoYylic acid, O.5 g of 1-(5-quinolyl)-5-(2,6-dimethoxyphenyl)-3-pyrazol~rArhonyl chloride and 0.7 g of potass~um hydroxide are dissol~ed in 25 ml of dichloromethane i~
the presence of 0.1 g of Aliquat 336-.
o The reaction mixture is stirred overr.ight at _oom temperature, 0.7 g of potassium hydroxide is zdded znd the mixture is stirred for 4 hours. It is filtered and 0.2 g of the expected product is obtAin~.
M.p. ~ 260~C
(S)-2-{~1-(4-Chloro-l-naphthyl)-5-(2,6-dihydroxyphenyl)-3-pyrazolyl~rArho~ylamino}h~YAnoic acid.
(I): R=H ; n=0 ; X' = H ; X = (CH2)3-CH3 Z = O H : Rl= I ~ ; Rlv = H
RV = H O ~ OH
0.3 g of 2-{[1-(4-chloro-1-naphthyl)-5-(2,6-di-methoxyphenyl)-3-pyrazolyl]carbonylamino}h~YAno czcidis dissolved in 6.7 ml of dichloromethane and the mixtuse is cooled to -70~C. 5.7 ml of boron tribromide, dissolved in 20 ml of dichlormethane, are added dropwise and the reaction mixture is left for 2 hours at -70~C. It is allowed to return to room temperature, and 12 ml of water are then added while cooling. Concentrated NaOH is added to pH 14. The aqueous phase is washed with ether and o brought to pH 2, the product is extracted with ethyl acetate and the organic phase i8 dried over sodium sulphate, filtered and evaporated. The residue is crystallised from diiso~ u~yl ether.
m = 0.13 g M.p. > 260~C
2-{~1-(1-Naphthyl)-5-(2,6-dimethoxyphenyl)-3-pysazolyl~-carbonylamino}-2-adamantanecarboxylic acid.
R=H ; n = O ; X-C-X'= ~
Z = OH ; RI= I X ; RIV = H
RV = H3CO ~ OC~3 0.107 g of sodium hydroxide in 1.36 ml of wzter ~nd 0.51 ml of tetrahydrofuran are cooled to 0~C. 0.52 g of 2-2mino-2-adamantAn~cA~h~ylic scid is added n a single portion, and 0.53 g of 1-(1-naphthyl)-5-(2,6-di-methoxyphenyl)-3-pyrazolec~ho~yl chloride, dissolved ~n 3 ml of tetrahydrofuran, is then added dropwise. ~he mixture is left for 10 minutes, and the same _~our.t of the above acid chloride, in 3 ml of tetrahydrofuran, is added again; simultaneously, 1.32 ml of 2N sodi~m hy~roxide a_e added. The reaction mixture is left fo= 4 days at room temperature; successively, ice-cold water is added and concentrated hydrochloric acid is added to pH 1, and the precipitate is filtered off. The crystals are washed with diiso~pyl ether.
m = 0.48 g M.p. > 260~C
Methyl 2-{tl-(1-naphthyl)-5-(2,6-dimethoxyphenyl)-3-pyrazolyl]carbonylamino~-2-adamantanecarboxylate.
(I) : R=H ; n=0 ; X-C-X'= ~
Z = OCH3 ; RI = ¦ ~ ; RIV = ~ ;
RV = H3CO ~ OCH3 ~ ~' 0.5 g of the compound prepsred in Example 11 is dissolved in 34.6 ml of anhydrous tetrahydrofurzn znd 4 ml of dimethylformamide. 3.5 ml of water and 0.208 g of caesium cArho~Ate are added and the reaction mix~ure ~8 left at room temperature for 1 hour. It is ~on~entrated under vacuum and treated azeotropically with toluene. The residue is taken up in 5 ml of tetrahydrofuran. 0.6 m' of methyl iodide is added and the reaction mixture is left for 1 hour at room temperature. It is concentrated under ~acuum, the residue is taken up in water, the mixture s stirred and the precipitate i~ separated by filtration.
The precipitate is washed with water and with pentane.
m - 0.38 g N.p. 242-244~C
- ~166~Q3 2-{tl-(7-Chloro-4-quinolyl)-5-(2,6-dimethoxyphenyl)-3-pyrazolyl]csrbonylamino}-2-adamantAnecArboxylic acid.
(I) : R=H ; n=0 ; X-C-X'= ~
Z = OH : Rl~ I ~ ; RIV = ~ ;
RV = H3CO ~ OCH3 Using the procedure employed in Example 8, and replacing the acid chloride by l-(7-chloro-4-quinolyl)-5-(2,6-dimethoxyphenyl)-3-pyrazole~rhonyl chloride, the intermediate compound of formula:
,N ~~~~O
~' is obtAine~, the melting point of which is 249~C.
0.1 g of this intermediate is dissol~ed in 5 ml of dichlormethane; 5 ml of trifluoroacetic acid are added and the mixture is left for half an hour at room temperature. It is concentrated under vacuum to o~tain the expected compound.
m = 0.080 g '~166903 M.p. ~ 260~C
By repeating any one of the procedures desc_~bed in Examples 1 to 13, the compounds shown in Tables 1 to 15 below were prepared. In these tables, R3, when it is 5 used, .e~.~aents the groups X
- (CH2)n - C--C-- Z
X' O
21~903 .
CO
~ N' N
.
~1 F~r~ lC /R M.p.; C
n~ --N C~ . nn \R3 s;~lvent ~2~
15 - NH-CH2-CO2 Et 116 ~2~
16- NH-(CH2)2-C02 H - 17û
L~20 17C~3-(CH2)3- ,CH-C~2H S 7û
-NH CH
18(CH3)2-CH-fH-CO2H S 152 -NH ~2 19C6H5-CH2- 1C~-C~2H S 214 -NH ~2 20C6H5-(CH2)2- 1CH-CO2H S 79 -NH CH
-NH ~2 22NH2-(CH2)4- ,CH-CO2H S 150 -NH ~2~ (HCl) 21~ 9 0 i~
~C-NH-(CH2)3-fH-CO2H S 125 H2N -NH CH (HCl) 24HO2C (CH2)2-fH-co2H S ~020 25,~N~Co2H S '12 iPr, O
~ ~ CH2--CH--C02H
26 r ~ s 207 NH L~20 H
CHr CH--C02CH3 ~ \ H iPrOH
28 N ~ - NH S EtOH,H2O
29 ~ RS 84 ~ Pn,~t20 H~ C O2H
~N--CN--CN 4~\
Example R~ R~ R5 R~5 R"5 z "~ P-; ~C
crystal.
solvent EtO~
31 H H 4 No2 H H OCH3 69 Hx iPr20 33 H H 2-C1 4-Cl H O~ 108 iP~2O
34 H H 2-CH3 4~CH3 6-C~3 OH 120 iPr20 3~ H H 2-OCH3 6-OCH3 H O~I 99 iPr2O
36 1 F H 2-P H H ou 203 ~2~
37 4-P H ~Cl H H OH 90 Pn ~2~
i~2o 40, 4-Cl H 4-CI H H OE~ 98 Pn ~16~90~
41 ~ CH3 H 4-OCH3 H H OH 94 i~2o 42 4~3 H 4-Cl H H OH 84 P~
iPr20 44 2-C1 4-Cl 4-Cl H H OH 110 Pn 4S 2-Cl S-Cl 4-CH3 H H OH 90 Pn 46 2-CH3 5-F 2-Cl H H OH 100 Pn 47 3-a 4 Cl H H H OH 83 -48 3-C1 4-Cl 4 CH3 H H OH 100 Pn 49 4-t-Bu H H H H OH 88 C~
Hx S1 4-NH2 H H H H ~C~3 9~
Hx 52 ~NH2 H H H H ONa 155 he compound~ of Table 2 are all of S configuration.
- ~166~03 C--N--CH--C~2 ~R6 ,N
&le ~ R,~' R Z R6t2~1~1.yl C* M.p; ~
solven~
53 H H H OH H 1 S 2"1 ~2 54 H H H OH H 2 R ' '4 ~2 E~
56 H H H OH C:l 1 R.S 212 ~2 57 H H H OH C:l 2 R S 196 ~2 E~
Pn 2-C1 5-Cl H OH H 1 S 115 61 2~ 5-Cl H OH H 2 S lOS
Hx 62 2-C1 5n H OH Cl 1 R S 1;9 Hx 63 2-a 5-Cl H OH a 2 R S '~'1 iPr70 ~1669()~
o4 3-a ~a H OH H 1 S ~_1 3-a 4 Cl H ONa H 2 S 140 ~tOH
TaBL~ 4 ~ ~ /C~3 C--N--CH--CH2--c~
RV~ ~N coz \ CH3 N
~ple M.p.; ~C
Z RV C~crys~l.
solvent 66 H H OH ~ S 86 67 H H OH ~ S 107 oc~3 68 H H OH ~._OCH3 oc~3 69 H H OH ~t S 16S
\~ ~ (Ha ~ 2166903 ~F H OH _~ S 174 71 1 F H OH ~t--a S 92 72 l F H OH ~ S 96 73 ~Cl H OH {~--a S 89 74 4-t-Bu H OH ~ S 88 2-Cl S~ OH ~C~3 i 2~25O
76 3-Cl 4 Cl OH ~ S 72 77 3 Cl 4 Cl OH {~C~3 98 78 3~ 4 Cl OH --~CH3 Pn 79 3-Cl ~Cl OH ~ S 135 2-C1 5 Cl OH ~ S 2_5 21~6903 T~BLE 5 C-N-C~-COOH
~J~N~N C~3 C~3 R~
r.~."~.l, ~ R'~, Rv M.p.; ~C
CryStA~ At i 1~1 solver,.
oc~3 81 H H ~ 161 OCH~ O
rcH3 82 H H ~ 01 H3coJ~oc~3 AcOE~
~ ~,o 84 ~F H ~3 59 1 Cl H _~} 100 86 4-t-Bu H ~ 88 bJ' Y~x 87 3-C1 4-C1 ~ 83 ~ Y.7c 88 3-C1 1 Cl ~ 90 The compounds of Examples 81 to 88 are of S
conf iguration .
~fi, - ~-R3 ~1 ~
EKalple ~d~l~yl ~ 2; ~C
No R3 RS E~i~inn C~ crystal.
solvent 89 XO-CH2-fH-CO2H H 2 S '70 ~ AcOEt (cH3)2-cH-c~2-cH CO2H H 1 S 88 91 ~c~3 ~ 1 S ~06 CH3--CH2--CH--f~C02H L~20 92 CH3-(CH2)2- ,CH-C02H H 1 S 198 ~~
93 CH3 (CH2)3-CIH CO2H H l RS 92 CH
94 C~3 (CH2)3 ~c~i CO2H H 1 R 190 L~20 --~;H-C02H
,~ H 1 R S 2~6 L~ iPr~O
96 (CH3)3 C-fX-C02H E~ 1 S '30 iP~20 97 C~3 ~CH2)2 ,C~I-CO2H 6-OCH3 2 S 92 98 CH3-(CX2)3-C~H C~2H 6-OCH3 2 S 98 CH
99 (cH3)2-cH-f H-C~2H 6-OCH3 2 S 95 100 (CH3)2 CH CH2 ~CH C~2H 6-OCH3 2 S 95 Hx 101 (CH3)2-CH-CH2 CH-CO2H H 2 S 100 102 C6HS-(CH2)2- ,CH-C02H H 2 S 120 103 C6HS-CH2 cH-co2H 6-OCH3 2 S 95 Hx HN~
104 ~C NH-(C~2)3 fH CO H H 2 S 175 H N AcOEt H N~
105 C~NH-(CH~)3- ~CH'C02C~3 H 2 S 110 H N
~C~2 C~ CO~H
106 ~I H 2 S 200 AcOEt 107 ~ IH cH2-s-cH2-l H H 2 S 217 C02Na COCH3 EtOH
- ICH-CH2-CH2~ H 1 S 100 ~166903 R5~ 1~ COON R6 R~
FY~Fle M.p.; C
n~ R4 R6 RIv RS C* solver.~ ~
109 H Cl a Cl R S 1''~
Elx 110 F ~ a ~ s llo Hx 111 F Cl a . c! R S 100 Hx 4~
co~R ~co~/R
)~ ~N )~ ~N\
RI Ia E~ca~le ~R3 ~-P~; ~C
No RI RIa -N\ RVC* ~y ~dl R solvent ~H2_ C6~S-Cl ~-C~2~ ~
1l2 ~ --NH F S 158 ~2 ~ I ~ ¦
3 ~I C6H5~CH'~IC~~¦ S 130 ~I CO~ ~ L~20 4 ~D (C113)2-CN2 Cli-C~2~ ~ 5 80 ~H2_ --2--CH-CO H ~
1l5 ~I b ~ R S 120 C~2H 4~ ~c 117 ~ 2 -N- ICH-(cH2)3-cH3 ~ S 69 21~6 903 H oc~3 118 !3 C02H O~oc~ 1J0 9 ~cl -N-f~O ccYl CH
120 ~ f~ ocY~
121 fH2 f -a ~oc~3 109 -122 ~D HN-fH~ ~ocY~
216690s~
TAB~E 9 ,b b,D
Fy~A~ltrle M.p.; C
n~ -R3C* Crys~A~
solvent 123 (CH3)2-CH-CI H-C~2H S 200 ~-~2~
124 C6HS-cH2-fH-co2H S 110 ~0 o R
C-l-R3 FY,A-r~rle R M.p.; ~C
n~ I crys~lli~
-N-R3 solu~nt 125 C6HS-ClH-c02H 115 NH-- Pn 126 (CH3)2-C~-fH-C02H 110 NH-- ~,~
' 21~6~03 127C~3-(CH2)2-C~-COoH 90 NH- P~
128(C~3)2-c~-cH2-fx-co2H 100 NH- Hx 129CH3-(CH2)3-CH-CO2H
NH- Ph 130C6HS-cH2-lcH-co2~ lC0 NH- Pn The compounds 125 to 130 are of S configuration.
~ IR
R. ~ R~
Ex n~ ~ ~ RS R~5 R"s C* c~al.
-N-~3 solvent 131(cH3)2-cH-~cH-co2H H H H H S 1;0 NH-- ~c 132CH3-(CH2)3-lCH-cO2H H H H H S 100 NH- Pn 133(cH3)2-cH-cH2-~CH-cO2H H H H H S 2~0 ~H- Pn 134C6H5 - CH~- ~CH-C02H H H H H S 110 NH-135cH3-(cH.)3-~cH-co2H H 24cH3 6~C~3 H S 113 NH-21669~3 .
136 l H 24CH3 6~CH3 H S250 ~ Pn 137 l H 2~CH3 6-OCH3 H ~S136 ~ Pn -N-fH~ H 2~XC~3 6-OCH3 H S ~2 139 N~ H 24CH3 6~CH3 H 122 140 1 A >260 -N~ H 24CH3 6-OCH3 H Hx 141 ~ D--~ 112 -~-fH-cH2 ~ H 24CH3 6-OCH3 H SL~2 -N-lcH-(CH2)3-C~2H H 2~CH3 6~CH3 H S ~2 CO,H
143~ fH3 116 -N-f ~ H 2 4CH3 6-OCH3 H RS ~2 144 -N~ H 24CH3 6-OCH3 H - >260 CO2H Hx 145 H A >260 -N ~ CH3 H 2-OCH3 64CH3 H . Hx 146 1 r--\ >260 -N~H V H 24CH3 6-OCH3 H ~S Hx 147 ~ ~ ~260 -N- ICH~ H 2~CH3 6-OCH3 H S Hx ~1~690353 L~ iPr2O
149 -Nbco2H H 24CH3 4-OCH3 '10 150 ~N CH~) H 24CH3 54CH3 H 2''3 lSl ~ fH--O H 2-OCH3 4 OCH3 H S iPr1O
H
152 -N--lH-CO2H H 24CH3 64CH3 H R 2¢7 o -N 7~1 H 24CH3 6-OCH3 H Y.x 154 co~O H 2~CH3 6~CH3 132 155 IH ~ 114 -N7~,/ H 2-OCH3 6-OCH3 H Hx CO,,H
-N-ICH-c-(cH3)3 H 2-OCH3 6-OCH3 H S h~2o 157 H ~ CH3 244 -N-IC--CH H 2-OCH3 64CH3 H . iPr~O
CO.,H
158 EjI 106 _N_~H-(CH2)S-cH3 H 2~CH3 6~C~I3 H R S Hx 159 IH ~ H H S >260 -N~HV 24CH3 6-OCH3 H~x 21fi6gO3 160 1 >'60 --N-CH--O H2-OCH3 6-OCH3 H R Hx 161IH ~ . 174 -N7~ H2)11 H2-OC~3 6-OCH3 H H7c 162H A >260 -N ~ H2-OCH3 6-OCH3 H R SEtOH
163 ~ H2-OCH3 6-OCH3 H 24~
-~- ,C~
164-N-~;H--O H2-oc2H5 6~C2H5 H 2'_ 165-~7CN CH2~ 2-OCH3 6-OCH3 Et~O
CO.H
-X7~,D 2-OCH3 6~CH3 CH ~a 167-X 7CN-H H2~CH3 6-OCH3 H Et ~O
CO2H . HCI
168 -N~l H2-oc2H5 6-OC2H5 H iPr2O
~H3 169 ~ 3 H 2-OCH3 6-OCH3 H - >_60 21~6903 .
170 ~ >260 -N7~J H 2~CH3 6-OC~3 H R S C~,a, CO.,H -E~20 171,~ C7 >260 -N~ H 2-OCH3 64CH3 H iPr2O
172 /~ 120 -N~_J H 24CH3 64CH3 H S Pn 173-N-C~H--a H 2-OCH3 64CH3 H R S 81 ct~2CH3 Pn 174 ~ r ~260 -N- ~CH- ~_ H 24CH3 64CH3 H R SiPr~O.
175fH3 ,~ ., -N-ICH--~J H 24CH3 6-OCH3 ~ R S Hx CO,2H
176 ,~ ~50 )~ J~J, H 2~CH3 6-OC~3 H R S L~2O
H02C ~ -177 ~ H 2~CH3 6-OCH3 H R S L~2O
178~ C02H H 24CH3 44CH3 6-OCH3 R S 2'~9 ~1 L~20 179 ~ ~ H S ~260 ~ 24CH3 44CH3 6-OCH3 ~2~
180 --N~-cO2H 4-C1 24CH3 64CH3 H RS 125 L~ Hx 181 ~ 120 N fH (CH2)3~H3 4 Cl 24CH3 64CH3 H S Hx '~1669~3 82 /~ l~O
-N~,~ 4 Cl24CH3 64CH3 H S CH
183 H ~ H 2-CH3 6-CH3 H '80 - Et20 184 -N-C H 2~CH3 64CH3 H ~
185 Y H '06 -~-CH2~~2H 2~CH3 64CH3 H - L~2O
186 -N~ 4-C1 24CH3 6~CH3 H - >260 iPr~O
~ ~ 180 187 -N 7~ ~ H 24CH3 6-OCH3 H - McoH
C02H -H ~O
s~ , ~260 HN~J H 2~CH3 6~CH3 H R S Et~O
coo~3 R ~
189 -N-fH-CH2-O H 24CH3 64CH3 H S CH
NH- H 2~CH3 64CH3 H R S CH
21~5903 R'~R3 Ex. ~ C* M.p; ~C
n~ R~ R',~ R'~ -N-R3 R5 R'5 R~5 crystAl, solvent f~2~ 79 191 H H HCH3-(CH2)3-CH 3-OCH3 4~ 3 H S Y.x NH-f~2~ 69 192 H H HCH3-(CH2)3-CH 3 OCH3 4~CH3 ~-~C~3 S Y,x NH-f~2~ 90 193 H CH3-(CH2?3-~C~H2~C~3 4~CH3 6 OCH3 NH--194 H H CH2-NH- 3 3 H R S ~x f~2~ 9~
1953~C1 4~ HCH3-(CH2)3-CH 2-OCH3 6 OCH3 H S Y,x NH-196 3 Cl 4-Cl HQ~H_CO2H 2~CH3 ~OCH3 H R S 100 NH--i 2166903 197 2-C1 6-Cl H CH3-(cH2)3 cH 2~3 NH-f~2}
1982-C1 5-Cl H CH3-(CH2)3-C 2 0CH3 6-OCH3 H S Pn ~;O2H 85 199 3-C1 4-Cl H c6H~(cH2)2-cH-NH- H H H S C~
f~2~ 78 200 3 a 4~ H CH3-(CH2)3-~CH H H H S Y,x NH-201 3-C1 4-Cl H ~L ICH-CO2H H H H R S Hx NH-202 4 H H CH3_(CH2)3$H H H H S Yx t-Bu NH-(CH3)2-CH-cH2 66 203 H H H H2N-,C,-¢H H H H S Yx o NH-204 3-Cl 4 Cl H CH3-(CH2)3-CI; 2 OCH3 6~CH3 H S y~O
NaOOC
f~2~ 98 20S 3-C1 4-Cl H CH3-(CH2)3-CH 2 OCH3 4~ 3 6 OCH3 S CH
NH-2 0 6 2-Cl S-Cl H -N-fH-(cH2)3-cH3 2-OCH3 6-OCEI3 H S 64 C02C~{3 '~i669n~
'07 2-C1 3-Cl ~Cl -~- CH-CO-~ 2~CH3 6~ 3 H R,S cu b 208 2-C1 3-C1 4-C~N I H (CH2)3 CH3 2 OCH3~OCH3 H Pn 209 2-Cl 4 Cl 6-Cl-N-ICH-(C82)3-CH3 2~ 3 6 OC~ H Pn CO,H
210 2-Cl 4 Cl 6-Cl--N--ICH-CO2H 24CH3 6~3 H R S CH
}~ 79 211 3-CF3 5 CF3 HN ICH (CH2)3 CH3 2~H3 6~3 H Pn 212 3-CF3 5-CF3 H _N~;-co2H 2~CEI36~ 3 H R S
H
213 2-C1 3-Cl H_,~_ IC8-CO2H 2~C~I36 OC~3 H R~S HX
2~4 2-Cl 3~1 HN ~ H-(CB2)3 CH3 2~CH36 OCEI3 H Pn 215 2-C1 5-Cl H ~}~ 4-N02 H ~
216 2-C1 3-Cl H -N~ 2-OCH3 6-OCH3 H Hx 217 3 CF3 S~:3 H -N~ 2~ I3 6-0CH3 H S Hx C~2H
218 3-CF3 5 CF3 -N-CH2-co2H 2-0CH36~C~13 C~I
/~ 110 219 2-Cl 4 Cl 6-Cl --N~ 2~C~I3 6-OCH3 ~ H.x ~o 3-C1 4-Cl H -N-f Cli 2-C1 6-Cl H 240 ~l 3-Cl 4Cl HN CIH (CH2)3 CH3 2-C1 6-Cl H S 98 ~2 3-Cl '1 a H ~ f~9 2-C:1 6~ 0 ~3 3-Cl ~Cl H --Nb-CO2H 2-C1 6-Cl H ~ S p 224 2-a 4-a H --Nb-CO2N 2~3 6 OCH3 H R S ~, 225 2-Cl ~1 Cl HN-CIH-<CH2)3-CH3 2-OCH3 6-OCH3 H S 196 CO.H
226 3-CI 4-F H -N--CN-CO2N 20C~13 64~}3 H RS CH
227 3-Cl 4-Cl H --Nb-CO.H 2-F 6-F H R S L~r~O
228 3-Cl 4 Cl HN Cl H-(CH-)3 CH3 2-F 6-F H S Hx ~g 2-a s-a CO2N -~ 2-OC~I3 6~I3 H S 86 230 2-C1 6-Cl H -N-CH-CH2--0 2~OC~3 6~13 H S 268 ~166903 231 H H H -N-CH-(CH.)3-CH3 24CH3 4-OCH3 H Hx CO,H
232 H C~2H ~ 4-NO2 H H S 100 233 ~Cl H H --N--CH-Co2H 24CH3 6~I3 H R S 116 b ~ 169 234 4 Cl H HN cl H (CH2)3 CH3 24CH3 64C H3 H Hx 23S 2-Cl H H-N--lH-C02H 24C~3 H H R S
236 2~1 H HN ICH ~CH2)3 CH3 2~3 H H S
- 237 3 Cl 4-a H-N lH-C02H 24CH3 H Hx C~ ' ~ 85 238 3 Cl 4 a H~ CIH (CH~)3 CH3 24C~3 H H S Pn /___ 107 239 2-C1 5-Cl H -N~ 24CH3 6~ 3 H S Hx 240 3 Cl H -N-CH-~CH2)3-CH3 24C~I3 64CH3 S 96 CO.H
241 3-Cl H H--N--CH-CO.H 24CH3 64CH3 H R S C~
b ~ 83 242 3-Cl H H -N-cl H-(CU2)3-CH3 2-0CH3 64CH3 H S C~
~166903 243 3-C1 1 Cl H - N--CH-C02H 2 CH3 Y H R,S y b 244 3-Cl 4 Cl HN Cl H ~CH2)3-cH3 2~3 H H S 8S
245 3-C1 5-Cl H --N--CH-CO2H 2~CEI36 0C~3 H R S Yx 246 3-C1 5-Cl H N~ H (C~2)3 C~3 2~3 C~.3 H S PT~
247 H H H N~ H (CH2)3 C~3 2 OCH3 6~3 H S Pn ~ABLE 13 C--N--~.3 R'S R(I) Ex. R~ R'~ R~ IR C~~,~l;i~i~
-N-R3 solvent 248 2~C1;3 6~3 ~ ~ -a R 5 107 N C~2C~3 249 24CH3 6~3 ~ --Nbco ,H ~320 250 2W13 6~3 ~ -N-f~g~ R S ~' 1 251 2 0CH3 6 0CH3 ~5~ --Nbco2H R S L~l2o 252 2~0CH3 60CH3 1~ -~-fCH~O l17 253 2~H3 6~3 ~ -~N-f ~0 s L~20 2S4 2-oCH3 6~)CH3 b(~ -N~ L~020 co2~
255 2~C~3 6~0CH3 b~ f~ ~O S L~O
256 2 oCH3 6~3 ~ Co2H R S 118 /~ 128 257 2~CH3 64C~3 0 --N~_~ S P;l ~ -N-cH-(cH2)3-c~
258 24C~3 ~XH3 ~ C02H S Pn 259 24C~3 6~3 ~0 -~-fcHo~~ ~260 260 24C~3 6~0CH3 ~o H~ - L~r20 261 2 OCH3 6~3 ~NN -N~ L~_O
co2 262 2~3 64~I3~ ,S -N~l 26 CO~I
~ C--N--R3 H3C ~ N
i~N
~1 FY~ e . M.p.; ~, n~ R3 C~CrYSt~ At;~
solvent 263 C5HS_CH2_ ICH_C~2H S 105 264 C5HS_CH2 CI H_C~2CH3 S 80 2166~03 o R
OCH3 ll--N--R3 N~ lf OC}~3~
~nplc ~R M.p.; ~C
n~ -N C~ cryst~ tiOn R3 solvent H, I10 255 -N-cH-(cH2)3-cH3 S iPr O
H 1'0 266 --N--lCH-C~2H R S L~.'~O
267 ~ N~_ S CH
Claims (4)
1. A 3-amidopyrazole of formula (I):
in which:
x is hydrogen;
X' is a C3-C7 cycloalkyl group; or X and X', together with the carbon atom to which they are linked, form a C3-C12 cycloalkyl group optionally substituted by a C1-C3 alkyl;
RI represents:
a phenyl group substituted by Ra, R'a and R"a wherein Ra, R'a and R"a each independently represent a hydrogen atom, a halogen atom, a hydroxyl, a linear or branched C1-C4 alkyl group, a C1-C4 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a nitro group, a carboxyl group or an amino group;
a tetrahydronaphthyl group;
a naphthyl group substituted by Ra, R'a and R"a as defined above; or a quinolyl or isoquinolyl group optionally substituted by Ra, R'a and R"a as defined above;
R represents hydrogen or linear or branched C1-C4 alkyl;
n represents 0, 1, 2 or 3;
z represents a hydroxyl group;
a C1-C6 alkoxy group;
an oxygen atom substituted with a carboxylic acid-protecting group, wherein the carboxylic acid-protecting group is selected from the group consisting of tert-butyl, benzyl, benzyl substituted with a halogen atom, C1-C6 alkyl, trifluoromethyl, trifluoromethoxy or carboxyl;
an amino group; or a nitrogen atom substituted with a carboxyalkyl in which the alkyl is a linear or branched C1-C6 group;
RIV represents a hydrogen atom, a halogen atom or a C1-C6 alkyl;
RV represents:
a phenyl group substituted by R5, R'5 and R"5, where R5, R'5 and R"5 each independently represent a hydrogen atom, a halogen atom, a linear or branched C1-C4 alkyl, a hydroxyl, a C1-C4 alkoxy, a nitro, a trifluoromethyl, a trifluoromethoxy, a cyano, an amino, a carboxyl, a C1-C4 carboxyalkyl or a phenyl;
a naphthyl group unsubstituted or substituted with a C1-C4 alkyl;
a pyridyl group;
a styryl group unsubstituted or substituted with a C1-C4 alkyl;
or alternatively RIV and RV considered together represent:
a group in which the phenyl group substitutes the pyrazole at position 5 and the group -(CH2)i - in which i = 1 to 3 substitutes the pyrazole at position 4; W1 W2 and W3 substitute the benzene ring and independently represent hydrogen, a halogen or a hydroxyl group;
or one of its pharmaceutically-acceptable salts with organic or inorganic acids or with inorganic or organic bases.
in which:
x is hydrogen;
X' is a C3-C7 cycloalkyl group; or X and X', together with the carbon atom to which they are linked, form a C3-C12 cycloalkyl group optionally substituted by a C1-C3 alkyl;
RI represents:
a phenyl group substituted by Ra, R'a and R"a wherein Ra, R'a and R"a each independently represent a hydrogen atom, a halogen atom, a hydroxyl, a linear or branched C1-C4 alkyl group, a C1-C4 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a nitro group, a carboxyl group or an amino group;
a tetrahydronaphthyl group;
a naphthyl group substituted by Ra, R'a and R"a as defined above; or a quinolyl or isoquinolyl group optionally substituted by Ra, R'a and R"a as defined above;
R represents hydrogen or linear or branched C1-C4 alkyl;
n represents 0, 1, 2 or 3;
z represents a hydroxyl group;
a C1-C6 alkoxy group;
an oxygen atom substituted with a carboxylic acid-protecting group, wherein the carboxylic acid-protecting group is selected from the group consisting of tert-butyl, benzyl, benzyl substituted with a halogen atom, C1-C6 alkyl, trifluoromethyl, trifluoromethoxy or carboxyl;
an amino group; or a nitrogen atom substituted with a carboxyalkyl in which the alkyl is a linear or branched C1-C6 group;
RIV represents a hydrogen atom, a halogen atom or a C1-C6 alkyl;
RV represents:
a phenyl group substituted by R5, R'5 and R"5, where R5, R'5 and R"5 each independently represent a hydrogen atom, a halogen atom, a linear or branched C1-C4 alkyl, a hydroxyl, a C1-C4 alkoxy, a nitro, a trifluoromethyl, a trifluoromethoxy, a cyano, an amino, a carboxyl, a C1-C4 carboxyalkyl or a phenyl;
a naphthyl group unsubstituted or substituted with a C1-C4 alkyl;
a pyridyl group;
a styryl group unsubstituted or substituted with a C1-C4 alkyl;
or alternatively RIV and RV considered together represent:
a group in which the phenyl group substitutes the pyrazole at position 5 and the group -(CH2)i - in which i = 1 to 3 substitutes the pyrazole at position 4; W1 W2 and W3 substitute the benzene ring and independently represent hydrogen, a halogen or a hydroxyl group;
or one of its pharmaceutically-acceptable salts with organic or inorganic acids or with inorganic or organic bases.
2. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
3. A pharmaceutical composition according to claim 2 in the form of a dosage unit.
4. A pharmaceutical composition according to claim 3 wherein the effective amount is from 1 to 250 mg the compound or a pharmaceutically acceptable salt thereof.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9010486A FR2665898B1 (en) | 1990-08-20 | 1990-08-20 | DERIVATIVES OF AMIDO-3 PYRAZOLE, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
| FR9010486 | 1990-08-20 | ||
| CA002049514A CA2049514C (en) | 1990-08-20 | 1991-08-20 | 3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002049514A Division CA2049514C (en) | 1990-08-20 | 1991-08-20 | 3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2166903A1 CA2166903A1 (en) | 1992-02-21 |
| CA2166903C true CA2166903C (en) | 1998-09-01 |
Family
ID=9399742
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002166903A Expired - Fee Related CA2166903C (en) | 1990-08-20 | 1991-08-20 | 3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them |
| CA002166902A Expired - Fee Related CA2166902C (en) | 1990-08-20 | 1991-08-20 | 3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them |
| CA002166901A Expired - Fee Related CA2166901C (en) | 1990-08-20 | 1991-08-20 | 3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them |
| CA002049514A Expired - Fee Related CA2049514C (en) | 1990-08-20 | 1991-08-20 | 3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002166902A Expired - Fee Related CA2166902C (en) | 1990-08-20 | 1991-08-20 | 3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them |
| CA002166901A Expired - Fee Related CA2166901C (en) | 1990-08-20 | 1991-08-20 | 3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them |
| CA002049514A Expired - Fee Related CA2049514C (en) | 1990-08-20 | 1991-08-20 | 3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them |
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| JP (1) | JP2694932B2 (en) |
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| AR (1) | AR248133A1 (en) |
| AT (1) | ATE187167T1 (en) |
| AU (1) | AU646683B2 (en) |
| BR (1) | BR9103550A (en) |
| CA (4) | CA2166903C (en) |
| CZ (1) | CZ281864B6 (en) |
| DE (1) | DE69131813T2 (en) |
| DK (1) | DK0477049T3 (en) |
| ES (1) | ES2142798T3 (en) |
| FI (1) | FI104170B (en) |
| FR (1) | FR2665898B1 (en) |
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| HK (1) | HK1005136A1 (en) |
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| NZ (1) | NZ239476A (en) |
| PL (1) | PL169085B1 (en) |
| PT (1) | PT98717B (en) |
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