U.S. patent application number 09/994076 was filed with the patent office on 2002-06-20 for salts of quinoline derivatives as nk3 antagonists.
This patent application is currently assigned to SmithKline Beecham S.p.A.. Invention is credited to Farina, Carlo, Giardina, Giuseppe Arnaldo, Grugni, M., Raveglia, Luca Francesco.
Application Number | 20020077335 09/994076 |
Document ID | / |
Family ID | 10784449 |
Filed Date | 2002-06-20 |
United States Patent
Application |
20020077335 |
Kind Code |
A1 |
Giardina, Giuseppe Arnaldo ;
et al. |
June 20, 2002 |
SALTS OF QUINOLINE DERIVATIVES AS NK3 ANTAGONISTS
Abstract
A compound of formula (I) or a solvate thereof, characterized in
that salt comprises a compound of formula (I) in anionic form and a
salting cation; a process for preparing such a compound, a
pharmaceutical composition containing such a compound and the use
of such a compound in medicine. 1
Inventors: |
Giardina, Giuseppe Arnaldo;
(Milan, IT) ; Farina, Carlo; (Milan, IT) ;
Grugni, M.; (Verbania, IT) ; Raveglia, Luca
Francesco; (Milan, IT) |
Correspondence
Address: |
GLAXOSMITHKLINE
Corporate Intellectual Property - UW2220
P.O. Box 1539
King of Prussia
PA
19406-0939
US
|
Assignee: |
SmithKline Beecham S.p.A.
|
Family ID: |
10784449 |
Appl. No.: |
09/994076 |
Filed: |
November 6, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09994076 |
Nov 6, 2001 |
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09077152 |
May 21, 1998 |
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09077152 |
May 21, 1998 |
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PCT/EP96/05210 |
Nov 22, 1996 |
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Current U.S.
Class: |
514/311 ;
514/312; 514/314; 546/156; 546/159; 546/167; 546/168 |
Current CPC
Class: |
A61P 37/08 20180101;
A61P 11/00 20180101; A61P 13/12 20180101; A61P 25/24 20180101; A61P
17/06 20180101; A61P 25/08 20180101; C07D 215/50 20130101; A61P
17/04 20180101; A61P 25/28 20180101; A61P 43/00 20180101; C07D
215/52 20130101; A61P 25/18 20180101; A61P 25/22 20180101; A61P
29/00 20180101; A61P 11/06 20180101; A61P 25/16 20180101 |
Class at
Publication: |
514/311 ;
514/312; 514/314; 546/156; 546/167; 546/168; 546/159 |
International
Class: |
A61K 031/47; A61K
031/4709; C07D 41/02 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 24, 1995 |
GB |
9524137.8 |
Claims
1. A compound of formula (I): 15or a solvate thereof, wherein Ar is
an optionally substituted phenyl, naphthyl or C.sub.5-7
cycloalkdienyl group, or an optionally substituted single or fused
ring heterocyclic group, having aromatic character, containing from
5 to 12 ring atoms and comprising up to four hetero-atoms in the or
each ring selected from S, O, N; R is linear or branched C.sub.1-8
alkyl, C.sub.3-7 cycloalkyl, C.sub.4-7 cycloalkylalkyl, optionally
substituted phenyl or phenyl C.sub.1-6 alkyl, an optionally
substituted five-membered heteroaromatic ring comprising up to four
heteroatom selected from O and N, hydroxy C.sub.1-6 alkyl, amino
C.sub.1-6 alkyl, C.sub.1-6 alkylaminoalkyl, di C.sub.1-6
alkylaminoalkyl, C.sub.1-6 acylaminoalkyl, C.sub.1-6 alkoxyalkyl,
C.sub.1-6 alkylcarbonyl, carboxy, C.sub.1-6 alkoxyxcarbonyl,
C.sub.1-6 alkoxycarbonyl C.sub.1-6 alkyl, aminocarbonyl, C.sub.1-6
alkylaminocarbonyl, di C.sub.1-6 alkylaminocarbonyl, halogeno
C.sub.1-6 alkyl; or is a group --(CH.sub.2)p-- when cyclized onto
Ar, where p is 2 or 3; R.sub.1 and R.sub.2, which may be the same
or different, are independently hydrogen or C.sub.1-6 linear or
branched alkyl, or together form a --(CH2)n-- group in which n
represents 3, 4, or 5; or R.sub.1 together with R forms a group
--(CH.sub.2)q--, in which q is 2, 3, 4 or 5, R.sub.3 and R.sub.4,
which may be the same or different, are independently hydrogen,
C.sub.1-6 linear or branched alkyl, C.sub.1-6 alkenyl, aryl,
C.sub.1-6 alkoxy, hydroxy, halogen, nitro, cyano, carboxy,
carboxamido, sulphonamido, C.sub.1-6 alkoxycarbonyl,
trifluoromethyl, acyloxy, phthalimido, amino, mono- and
di-C.sub.1-6 alkylamino, --O(CH.sub.2).sub.r--NT2, in which r is 2,
3, or 4 and T is hydrogen or C.sub.1-6 alkyl or it forms with the
adjacent nitrogen a group 16in which V and V.sub.1 are
independently hydrogen or oxygen and u is 0,1 or 2;
--O(CH.sub.2)s--OW in which s is 2, 3, or 4 and W is hydrogen or
C.sub.1-6 alkyl; hydroxyalkyl, aminoalkyl, mono-or
di-alkylaminoalkyl, acylamino, alkylsulphonylamino, aminoacylamino,
mono- or di-alkylaminoacylamino; with up to four R.sub.3
substituents being present in the quinoline nucleus; or R.sub.4 is
a group --(CH.sub.2)t-- when cyclized onto R.sub.5 as aryl, in
which t is 1, 2, or 3; R.sub.5 is branched or linear C.sub.1-6
alkyl, C.sub.3-7 cycloalkyl, C.sub.4-7 cycloalkylalkyl, optionally
substituted aryl, or an optionally substituted single or fused ring
heterocyclic group, having aromatic character, containing from 5 to
12 ring atoms and comprising up to four hetero-atoms in the or each
ring selected from S, O, N; X is O, S, or N--C.ident.N;
characterised in that salt comporises a compound of formula (I) in
anionic form and a salting cation.
2. A compound according to claim 1 of formula (A): S.sup.t-M.sup.t+
(A) or a solvate thereof, wherein; t is an integer 1, 2 or 3;
M.sup.t+ is a salting cation; and S.sup.t- is an anion provided by
an appropriate compound of formula (I) in claim 1.
3. A compound according to claim 2, wherein saltine cation M.sup.t+
is a metal ions or an organic cation.
4. A compound according to claim 2, wherein metal salting cation
M.sup.t+ is selected from aluminium, alkali metal or alkaline earth
metal ions.
5. A compound according to claim 2, wherein organic salting cation
M.sup.t+ is selected from ammonium or substituted ammonium
ions.
6. A compound according to claim 2, wherein saltine cation M.sup.t+
is a sodium ion.
7. A compound according to any one of claims 2 to 6, wherein t is 1
or 2.
8. A compound according to claim 1, being
(S)-(+)-N-(.alpha.-ethylbenzyl)-- 3-hydroxy-2-phenyl-4-quinoline
carboxamide sodium salt sesquihydrate.
9. A process for the preparation of a compound according to claim
1, which process comprises admixing a compound of formula (I) and a
source of salting cation; and thereafter, as required, preparing a
solvate of the salt so formed.
10. A pharmaceutical composition comprising a compound according to
claim 1, or a pharmaceutically acceptable solvate thereof, and a
pharmaceutically acceptable carrier.
11. A compound according to claim 1, or a pharmaceutically
acceptable solvate thereof, for use as an active therapeutic
substance.
12. The use of a compound according to claim 1, or a
pharmaceutically acceptable solvate thereof, in the manufacture of
a medicament for the treatment off the Primary, Secondary or
Further Disorders disclosed herein before.
13. A method for the treatment and/or prophylaxis of the Primary,
Secondary or Further Disorders in mammals which comprises
administering to the mammal in need of such treatment and/or
prophylaxis an effective, non-toxic pharmaceutically acceptable
amount of a compound according to claim 1 or a pharmaceutically
acceptable solvate thereof.
Description
[0001] The present invention relates to novel compounds, in
particular to salts of quinoline derivatives, to a process for the
preparation of such compounds, to pharmaceutical compositions
containing such compounds and to the use of such compounds and
compositions in medicine.
[0002] The mammalian peptide Neurokinin B (NKB) belongs to the
Tachykinin (TK) peptide family which also include Substance P (SP)
and Neurokinin A (NKA). Pharmacological and molecular biological
evidence has shown the existence of three subtypes of TK receptor
(NK.sub.1, NK.sub.2 and NK.sub.3) and NKB binds preferentially to
the NK.sub.3 receptor although it also recognises the other two
receptors with lower affinity (Maggi et al, 1993, J. Auton.
Pharmacol., 13, 23-93).
[0003] Selective peptidic NK.sub.3 receptor antagonists are known
(Drapeau, 1990 Regul. Pept., 31, 125-135), and findings with
peptidic NK.sub.3 receptor agonists suggest that NKB, by activating
the NK.sub.3 receptor, has a key role in the modulation of neural
input in airways, skin, spinal cord and nigro-striatal pathways
(Myers and Undem, 1993, J. Phisiol., 470, 665-679; Counture et al.,
1993, Regul. Peptides, 46, 426-429; Mccarson and Krause, 1994, J.
Neurosci., 14 (2), 712-720; Arenas et al. 1991, J. Neurosci., 11,
2332-8).
[0004] However, the peptide-like nature of the known antagonists
makes them likely to be too labile from a metabolic point of view
to serve as practical therapeutic agents.
[0005] International Patent Application Number PCT/EP95/02000
describes certain quinoline derivatives and describes inter alia
the preparation of the quinolines and their use in medicine. The
disclosures of PCT/EP95/02000 are relevant to the present
application only by virtue of Article 54(3) of the European Patent
Convention.
[0006] We have now discovered certain novel salts of the quinoline
derivatives of the compounds of PCT/EP95/02000. The new salts are
selective, non-peptide NK.sub.3 antagonists which are far more
stable from a metabolic point of view than the known peptidic
NK.sub.3 receptor antagonists and are of potential therapeutic
utility in treating pulmonary disorders (asthma, chronic
obstructive pulmonary diseases -COPD-, airway hyperreactivity,
cough), skin disorders and itch (for example, atopic dermatitis and
cutaneous wheal and flare), neurogenic inflammation and CNS
disorders (Parkinson's disease, movement disorders, anxiety,
psychosis). These disorders are referred to hereinafter as the
Primary Disorders.
[0007] The novel NK.sub.3 antagonists of the present invention are
also of potential therapeutic utility in treating convulsive
disorders (for example epilepsy), renal disorders, urinary
incontinence, ocular inflammation, inflammatory pain, eating
disorders (food intake inhibition), allergic rhinitis,
neurodegenerative disorders (for example Alzheimer's disease),
psoriasis, Huntington's disease, and depression (hereinafter
referred to as the Secondary Disorders).
[0008] The compounds of the present invention are also useful in
the prevention and treatment of disorders of the central nervous
system, such as schizophrenia; neurodegenerative disorders, such as
AIDS related dementia, senile dementia of the Alzheimer type and
Down's syndrome; demyelinating diseases such as multiple sclerosis
and other neuropathological disorders such as diabetic or
peripheral neuropathy, AIDS related neuropathy,
chemotherapy-induced neuropathy and neuralgia; respiratory diseases
such as, bronchopneumonia and bronchospasm; inflammatory diseases
such as inflammatory bowel disease, fibrositis, osteoarthritis,
rheumatoid arthritis; allergies such as eczema and rhinitis;
hypersensivity disorders such as poison ivy; ophthalmic diseases
such as conjunctivitis, vernal conjuctivitis and the like;
cutaneous diseases such as contact dermatitis, urticaria and other
eczematoid dermatitis; addiction disorders such as alcoholism;
stress related somatic disorders; reflex sympathetic dystrophy such
as shoulder/hand syndrome; dysthymic disorders; adverse
immunological reactions such as rejection of transplanted tissues
and disorders related to immune enhancment or suppression such as
systhemic lupus erythematosis; gastrointestinal (GI) disorders and
diseases of the GI tract such as disorders associated with the
neuronal control of viscera such as ulcerative colitis, Crohn's
disease; disorders of the bladder function; fibrosing and collagen
diseases such as scleroderma and eosinophilic fascioliasis;
disorders of the blood flow caused by vasodilation and vasospastic
diseases such as angina, migraine and Reynaud's disease; pain or
nociception, for example, that is attributable to or associated
with any of the foregoing conditions especially the transmission of
pain in migraine (hereinafter referred to as the `Further
Disorders`).
[0009] According to the present invention there is provided a
salted form of a compound of formula (I) (hereinafter also referred
to as `a Salt of the invention`): 2
[0010] or a solvate thereof, wherein Ar is an optionally
substituted phenyl, naphthyl or C.sub.5-7 cycloalkdienyl group, or
an optionally substituted single or fused ring heterocyclic group,
having aromatic character, containing from 5 to 12 ring atoms and
comprising up to four hetero-atoms in the or each ring selected
from S, O, N;
[0011] R is linear or branched C.sub.1-8 alkyl, C.sub.3-7
cycloalkyl, C.sub.4-7 cycloalkylalkyl, optionally substituted
phenyl or phenyl C.sub.1-6 alkyl, an optionally substituted
five-membered heteroaromatic ring comprising up to four heteroatom
selected from O and N, hydroxy C.sub.1-6 alkyl, amino C.sub.1-6
alkyl, C.sub.1-6 alkylaminoalkyl, di C.sub.1-6 alkylaminoalkyl,
C.sub.1-6 acylaminoalkyl, C.sub.1-6 alkoxyalkyl, C.sub.1-6
alkylcarbonyl, carboxy, C.sub.1-6 alkoxyxcarbonyl, C.sub.1-6
alkoxycarbonyl C.sub.1-6 alkyl, aminocarbonyl, C.sub.1-6
alkylaminocarbonyl, di C.sub.1-6 alkylaminocarbonyl, halogeno
C.sub.1-6 alkyl; or is a group --(CH.sub.2)p-- when cyclized onto
Ar, where p is 2 or 3;
[0012] R.sub.1 and R.sub.2, which may be the same or different, are
independently hydrogen or C.sub.1-6 linear or branched alkyl, or
together form a --(CH2)n-- group in which n represents 3, 4, or 5;
or R.sub.1 together with R forms a group --(CH.sub.2)q--, in which
q is 2, 3, 4 or 5.
[0013] R.sub.3 and R.sub.4, which may be the same or different, are
independently hydrogen, C.sub.1-6 linear or branched alkyl,
C.sub.1-6 alkenyl, aryl, C.sub.1-6 alkoxy, hydroxy, halogen, nitro,
cyano, carboxy, carboxamido, sulphonamido, C.sub.1-6
alkoxycarbonyl, trifluoromethyl, acyloxy, phthalimido, amino, mono-
and di-C.sub.1-6 alkylamino,
[0014] --O(CH.sub.2).sub.r--NT.sub.2, in which r is 2, 3, or 4 and
T is hydrogen or C.sub.1-6 alkyl or it forms with the adjacent
nitrogen a group 3
[0015] in which V and V.sub.1 are independently hydrogen or oxygen
and u is 0, 1 or 2;
[0016] --O(CH.sub.2)s--OW in which s is 2, 3, or 4 and W is
hydrogen or C.sub.1-6 alkyl: hydroxyalkyl, aminoalkyl, mono-or
di-alkylaminoalkyl, acylamino, alkylsulphonylamino, aminoacylamino,
mono- or di-alkylaminoacylamino; with up to four R.sub.3
substituents being present in the quinoline nucleus; or R.sub.4 is
a group --(CH2)t-- when cyclized onto R.sub.5 as aryl, in which t
is 1, 2, or 3;
[0017] R.sub.5 is branched or linear C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl, C.sub.4-7 cycloalkylalkyl, optionally substituted aryl,
or an optionally substituted single or fused ring heterocyclic
group, having aromatic character, containing from 5 to 12 ring
atoms and comprising up to four hetero-atoms in the or each ring
selected from S, O, N;
[0018] X is O, S, or N--C.ident.N; characterised in that the salt
comprises a compound of formula (I) in anionic form and a salting
cation.
[0019] Suitably, the salt is a compound of formula (A):
S.sup.t-M.sup.t+ (A)
[0020] or a solvate thereof, wherein,
[0021] t is an integer 1, 2 or 3;
[0022] M.sup.t+ is a salting cation; and
[0023] S.sup.t- is an anion provided by an appropriate compound of
the above defined formula (I).
[0024] Suitable saltine cations M.sup.t+ include metal ions and
organic cations, in particular pharmaceutically acceptable metal
ions and organic cations.
[0025] Suitable pharmaceutically acceptable metal ions include
those ions provided by aluminium, alkali metals such as lithium,
sodium or potassium, alkaline earth metals such as calcium or
magnesium.
[0026] Suitable pharmaceutically acceptable organic cations include
ammonium or substituted ammonium ions, for example those from lower
alkylamines such as triethylamine, hydroxy alkylamines such as
2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or
tri-(2-hydroxyethyl)-amine, cycloalkylamines such as
bicyclohexylamine, or with procaine, dibenzylpiperidine,
N-benzyl-.beta.-phenethylamine, dehydroabietylamine,
N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases
of the pyridine type such as pyridine, collidine, quinine or
quinoline.
[0027] A particular salting, cation M.sup.t+ is an alkali metal
ion, for example a sodium ion.
[0028] An appropriate compound of formula (A) is a compound which
is capable of forming an anion S.sup.t- and favourably includes
compounds of formula (A) which comprise acidic moieties, for
example those which comprise a carboxy group and/or a phenolic
hydroxy group.
[0029] Suitably, t is 1 or 2, for example 1.
[0030] Particular values for the variables of formula (I) are set
out below. It will be appreciated that any appropriate compound of
formula (I) comprising these variables will be characterised in
that it is capable of forming a anion S.sup.t-. Thus:
[0031] Examples of Ar are phenyl, optionally substituted by
hydroxy, halogen, C.sub.1-6 alkoxy or C.sub.1-6 alkyl. Examples of
halogen are chlorine and fluorine, an example of C.sub.1-6 alkoxy
is methoxy and an example of C.sub.1-6 alkyl is methyl.
[0032] Examples of Ar as a heterocyclic group are thienyl and
pyridyl.
[0033] Examples of Ar as a C.sub.5-7 cycloalkdienyl group is
cyclohexadienyl.
[0034] Examples of R are as follows:
[0035] C.sub.1-8 alkyl: methyl, ethyl, n-propyl, iso-propyl,
n-butyl, heptyl;
[0036] phenyl C.sub.1-6 alkyl: benzyl;
[0037] hydroxy C.sub.1-6 alkyl: --CH.sub.2OH, --CH.sub.2CH.sub.2OH,
CH(Me)OH;
[0038] amino C.sub.1-6 alkyl: --CH.sub.2NH.sub.2;
[0039] di C.sub.1-6 alkylaminoalkyl: --CH.sub.2NMe.sub.2;
[0040] C.sub.1-6 alkoxylalkyl: CH.sub.2OMe;
[0041] C.sub.1-6 alkylcarbonyl: COMe;
[0042] C.sub.1-6 alkoxycarbonyl: COOMe;
[0043] C.sub.1-6 alkoxycarbonyl C.sub.1-6 alkyl: CH.sub.2COOMe;
[0044] C.sub.1-6 alkylaminocarbonyl: CONHMe;
[0045] di C.sub.1-6 alkylaminocarbonyl: CONMe.sub.2,
CO(1-pyrrolidinyl);
[0046] halogen C.sub.1-6 alkyl: trifluoromethyl;
[0047] --(CH.sub.2)p-- when cyclized onto Ar: 4
[0048] Example of R.sub.1 and R.sub.2 as C.sub.1-6 alkyl is
methyl;
[0049] example of R.sub.1 together with R forming a
group--(CH.sub.2)q-- is spirocyclopentane.
[0050] Examples of R.sub.3 and R.sub.4 are methyl, ethyl, n-propyl,
n-butyl, methoxy, hydroxy, amino, chlorine, fluorine, bromine,
acetyloxy, 2-(dimetylamino)ethoxy, 2-(phthalimido)ethoxy,
aminoethoxy, 2-(1-pyrrolidinyl)ethoxy, phthalimido,
dimethylaminopropoxy, dimethylaminoacetylamino, acetylamino,
dimethylaminomethyl and phenyl.
[0051] Examples of R.sub.5 are cyclohexyl, phenyl optionally
substituted as defined for Ar above; examples of R.sub.5 as a
heterocyclic group are furyl, thienyl, pyrryl, thiazolyl,
benzofuryl and pyridyl.
[0052] A preferred group of compounds of formula (D) are those in
which:
[0053] Ar is phenyl, optionally substituted by C.sub.1-6 alkyl or
halogen; thienyl or a
[0054] C.sub.5-7 cycloalkdienyl group;
[0055] R is C.sub.1-6 alkyl, C.sub.1-6 alkoxycarbonyl, C.sub.1-6
alkylcarbonyl, hydroxy C.sub.1-6 alkyl;
[0056] R.sub.1 and R.sub.2 are each hydrogen or C.sub.1-6
alkyl;
[0057] R.sub.3 is hydrogen, hydroxy, halogen, C.sub.1-6 alkoxy,
C.sub.1-6 alkyl;
[0058] R.sub.4 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
hydroxy, amino, halogen, aminoalkoxy, mono- or di-alkylaminoalkoxy,
mono- or di-alkylaminoalkyl, phthalimidoalkoxy, mono- or
di-alkylaminoacylamino and acylamino;
[0059] R.sub.5 is phenyl, thienyl, furyl, pyrryl and thiazolyl.
[0060] A further preferred group of compounds of formula (I) are
those in which:
[0061] Ar is phenyl, 2-chlorophenyl, 2-thienyl or
cyclohexadienyl;
[0062] R is methyl, ethyl, n-propyl, --COOMe, --COMe;
[0063] R.sub.1 and R.sub.2 are each hydrogen or methyl;
[0064] R.sub.3 is hydrogen, methoxy, or hydroxy;
[0065] R.sub.4 is hydrogen, methyl, ethyl, methoxy, hydroxy, amino,
chlorine, bromine, dimethylaminoethoxy, 2-(phthalimido)ethoxy,
aminoethoxy, 2-(1-pyrrolidinyl)ethoxy, dimethylaminopropoxy,
dimethylaminoacetylamino, acetylamino, and dimethylaminomethyl.
[0066] R.sub.5 is phenyl, 2-thienyl, 2-furyl, 2-pyrryl, 2-thiazolyl
and 3-thienyl;
[0067] and X is oxygen.
[0068] A preferred sub-group of compounds within the scope of
formula (I) above is of formula (Ia): 5
[0069] in which:
[0070] R, R.sub.2, R.sub.3 and R.sub.4 are as defined in formula
(I), and Y and Z, which may be the same or different, are each Ar
as defined in formula (I).
[0071] A particularly preferred group of compounds of formula (Ia)
are those of formula (Ib) in which the group R is oriented downward
and H upward. 6
[0072] The compounds of formula (I) or their solvates are
preferably in pharmaceutically acceptable or substantially pure
form. By pharmaceutically acceptable form is meant, inter alia, of
a pharmaceutically acceptable level of purity excluding normal
pharmaceutical additives such as diluents and carriers, and
including no material considered toxic at normal dosage levels.
[0073] One particular compound is
(S)-(-)-N-(.alpha.-ethylbenzyl)-3-hydrox- y-2-phenyl-4-quinoline
carboxamide.
[0074] A substantially pure form will generally contain at least
50% (excluding normal pharmaceutical additives), preferably 75%,
more preferably 90% and still more preferably 95% of the Salt of
the invention or a solvate thereof.
[0075] One preferred pharmaceutically acceptable form is the
crystalline form, including such form in pharmaceutical
composition. In the case of salts and solvates the additional ionic
and solvent moieties must also be non-toxic.
[0076] Suitable solvates are pharmaceutically acceptable
solvates.
[0077] Examples of pharmaceutically acceptable solvates of a Salt
of the invention include hydrates, such as sesquihydrates.
[0078] The compounds of formula (I) may have at least one
asymmetric centre and therefore may exist in more than one
stereoisomeric form. The compounds of formula (A) include all such
forms and mixtures thereof, including racemates.
[0079] The invention also provides a process for the preparation of
a Salt of the invention, or a solvate thereof, which process
comprises admixing a source of S.sup.t- anions and a source of
salting cations M.sup.t+; and thereafter, as required, preparing a
solvate of the Salt of the invention so formed.
[0080] Suitable conditions for preparing the salt of formula (A)
include conventional salification methods, the particular
conditions used being dependent upon the particular nature of the
salting ions chosen, in particular the source of S.sup.t-.
[0081] Generally, the source of S.sup.t- ions and source of salting
cation M.sup.t+ are admixed in an alkanol, suitably an alkanol
containing water, at any temperature providing a suitable rate of
formation of the required product, usually at ambient temperature
or a slightly elevated temperature, such as a temperature in the
range of from 25 to 50.degree. C., for example 40.degree. C.
[0082] When the salting cation M.sup.t+ is a metal ion, a suitable
source of M.sup.t+ is a metal hydroxide, for example sodium
hydroxide for compounds where M.sup.t+ is sodium.
[0083] Suitable alkanols are C.sub.1-3 alkanols, for example
methanol.
[0084] When the solvent is an alkanol it may contain up to 25% by
volume, more usually up to 10% by volume, of water.
[0085] Conveniently, a solution of the source of salting cation
M.sup.t+ ions in water is admixed with a solution of the
appropriate compound of formula (I) in an alkanol.
[0086] The resulting product may be obtained by conventional
crystallisation/recrystallisation methods.
[0087] Conveniently, the produce is crystallised from the reaction
solvent Recrystallisation is conveniently effected using an
alternative solvent such as toluene or isopropanol or mixtures
thereof.
[0088] A suitable source of S.sup.t- ions is a compound of formula
(I) which comprises a carboxy group and/or a phenolic hydroxy
group.
[0089] A compound of formula (I) may be prepared by reacting a
compound of formula (III): 7
[0090] in which R', R'.sub.1, R'.sub.2 and Ar'are R, R.sub.1,
R.sub.2 and Ar as defined for formula (I) or a group or atom
convertible to R, R.sub.1, R.sub.2 and Ar, with a compound of
formula (II) 8
[0091] or an active derivative thereof, in which R'.sub.3,
R'.sub.4, R'.sub.5 and X' are R.sub.3, R.sub.4, R.sub.5 and X as
defined for formula (I) or a group convertible to R.sub.3, R.sub.4,
R.sub.5 and X, to form a compound of formula (Ic) 9
[0092] and optionally thereafter performing one or more of the
following steps:
[0093] (a) where R', R'.sub.1 to R'.sub.5, Ar' and X' are other
than R, R.sub.1 to R.sub.5, Ar and X, converting any one of R',
R'.sub.1 to R'.sub.5, Ar' and X' to R, R.sub.1 to R.sub.5, Ar and X
to obtain a compound of formula (I),
[0094] (b) where R', R'.sub.1 to R'.sub.5, Ar' and X' are R,
R.sub.1 to R.sub.5, Ar and X, converting any one of R, R.sub.1 to
R.sub.5, Ar and X to another R, R.sub.1 to R.sub.5, Ar and X, to
obtain a compound of formula (I),
[0095] (c) forming a salt and/or solvate of the obtained compound
of formula (Ic).
[0096] Suitable active derivatives of the compounds of formula (II)
are acid halides (preferably chlorides), acid azides or acid
anhydrides. Another suitable derivative is a mixed anhydride formed
between the acid and an alkyl chloroformate; another suitable
derivative is an activated ester such as a cyanomethyl ester,
thiophenyl ester, p-nitrophenyl ester, p-nitrothiophenyl ester,
2,4,6-trichlorophenyl ester, pentachlorophenyl ester,
pentafluorophenyl ester, N-hydroxy-phtalimido ester,
N-hydroxypiperidine ester, N-hydroxysuccinimide ester, N-hydroxy
benzotriazole ester; or the carboxy group may be activated using a
carbodiimide or N,N'-carbonyldiimidazole.
[0097] For example, in standard methods well known to those skilled
in the art, the compounds of formula (III) may be coupled:
[0098] (a) with an acid chloride in the presence of an inorganic or
organic base in a suitable aprotic solvent such as
dimethylformamide (DMF) at a temperature in a range from -70 to
50.degree. C. (preferably in a range from -10 to 20.degree.
C.),
[0099] (b) with the acid in the presence of a suitable condensing
agent, such as for example N,N'-carbonyl diimidazole (CDI) or a
carbodiimide such as dicyclohexylcarbodiimide (DCC) or
N-dimethylaminopropyl-N'-ethylc- arbodiimide and
N-hydroxybenzotriazole (HOBT) to maximise yields and avoid
racemization processes (Synthesis, 453, 1972) in an aprotic solvent
such as a mixture of acetonitrile (MeCN) and tetrahydrofuran (THF)
in a ratio from 1:9 to 7:3, respectively, at a temperature in a
range from -70 to 50.degree. C. (preferably in a range from -10 to
25.degree. C) (see Scheme 1), 10
[0100] (c) with a mixed anhydride generated in situ from the acid
and an alkyl (for example isopropyl) chloroformate in a suitable
aprotic solvent such as dichloromethane at a temperature in a range
from -70 to 50.degree. C. (preferably in a rance from -20 to
20.degree. C.).
[0101] It will be appreciated that a compound of formula (Ic) may
be converted to a compound of formula (I), or one compound of
formula (I) may be converted to another compound of formula (I), by
interconversion of suitable substituents. Thus, certain compounds
of formula (D) and (Ic) are useful intermediates in forming other
compounds of the present invention.
[0102] For example R'.sub.2 may be hydrogen and converted to
R.sub.2 alkyl group, for example methyl, by conventional amide
alkylation procedures (Zabicky, The chemistry of amides;
Interscience, London, 1970, p. 749). When X' is oxygen, it may be
converted to X sulphur by standard thioamide formation reagents,
such as P.sub.2S.sub.5 (Chem. Rev., 61, 45, 1961 or Angew. Chem.,
78, 517, 1966) or the Lawesson reagent (Tetrahedron, 41, 5061,
1985). When Ar' or R'.sub.5 is a methoxy substituted phenyl, it may
be converted to another Ar' or R'.sub.5 hydroxy substituted phenyl
by standard demethylation procedures via Lewis acids, such as boron
tribromide (Synthesis, 249, 1983) or mineral acids, such as
hydrobromic or hydroiodic acid. When R is an alkoxycarbonyl group,
for example methoxycarbonyl, it may be converted to another R, such
as ethoxycarbonyl by transesterification with an appropriate
alcohol at a temperature in a range from 20 to 120.degree. C.,
carboxy by hydrolysis in acidic or basic medium, aminocarbonyl,
alkylaminocarbonyl or dialkylaminocarbonyl by transamidation with
ammonia, a primary amine or a secondary amine in methanol as
solvent at a temperature in a ranae from 10 to 120.degree. C.,
optionally in the presence of a catalytic amount of NaCN (J. Org.
Chem., 52, 2033, 1987) or by using trimethylaluminium (Me.sub.3Al)
(Tetrahedron Letters, 48, 4171, 1977), hydroxymethyl by a selective
metal hydride reduction, such as lithium borohydride reduction
(Tetrahedron, 35, 567, 1979) or sodium borohydride reduction in
THF+MeOH (Bull. Chem. Soc. Japan, 57, 1948, 1984 or Synth. Commun.,
12, 463, 1982), alkylcarbonyl by acyl chloride formation and
subsequent reaction with alkylmagnesium halides in THF as solvent
at a temperature in a range from -78 to 30.degree. C. (Tetrahedron
Letters, 4303, 1979) or with alkylcadmium halides or dialkylcadmium
in the presence of MgCl.sub.2 or LiCl (J. Org. Chem., 47, 2590,
1982). Another group which R' as methoxycarbonyl can be converted
into is a substituted heteroaromatic ring, such as an oxadiazole
(J. Med. Chem., 34, 2726, 1991).
[0103] Scheme 2 summarizes some of the above described procedures
to convert a compound of formula (Ic) or (I) in which X' is oxygen,
R' is COOMe, Ar' and R'.sub.1 to R'.sub.5 are as described for
formula (I) to another compound of formula (I). 11
[0104] Solvates of the compounds of formula (I) may be formed by
crystallization or recrystallization from the appropriate solvent.
For example, hydrates may be formed by crystallization or
recrystallization from aqueous solutions, or solutions in organic
solvents containing water.
[0105] As mentioned before, the compounds of formula (I) may exist
in more than one stereoisomeric form and the processes described
herein may produce racemates as well as enantiomerically pure
forms. To obtain pure enantiomers, appropriate enantiomerically
pure primary or secondary amines of formula (IIId) or (IIIe) 12
[0106] are reacted with compounds of formula (II), to obtain
compounds of formula (I'd) or (I'e). 13
[0107] Compounds of formula (I'd) or (I'e) may subsequently be
converted to compounds of formula (Id) or (le) by the methods of
conversion mentioned before. 14
[0108] Compounds of formula (II) are known compounds or can be
prepared from known compounds by known methods.
[0109] For example, the compound of formula (II), in which X' is
oxygen, R'.sub.3, R'.sub.4 and R'.sub.5 are hydrogen is described
in Pfitzinger, J. Prakt. Chem., 38, 582, 1882 and in Pfitzinger, J.
Prakt. Chem., 56, 293, 1897; the compound of formula (II), in which
X' is oxygen, R'.sub.3 and R'.sub.4 are hydrogen and R'.sub.5 is
2-pyridyl is described in Risaliti, Ric. Scient., 28, 561, 1958;
the compound of formula (II), in which X' is oxygen, R'.sub.3 and
R'.sub.4 are hydrogen and R'.sub.5 is o-, m- and p-chlorophenyl,
o-fluorophenyl and 3,4-dichlorophenyl are described in Brown et
al., J. Am. Chem. Soc., 68, 705, 1946; the compound of formula
(II), in which X' is oxygen, R'.sub.3 and R'.sub.4 are hydrogen and
R'.sub.5 is p-methoxyphenyl is described in Ciusa and Luzzatto,
Gazz. Chim. Ital., 44, 64, 1914; the compound of formula (II), in
which X' is oxygen, R'.sub.3 and R'.sub.4 are hydrogen and R'.sub.5
is m-trifluoromethylphenyl is described in Shargier and Lalezari,
J. Chem. Eng. Data, 8, 276, 1963; the compound of formula (II), in
which X' is oxygen, R'.sub.3 and R'.sub.4 are hydrogen and R'.sub.5
is p-fluorophenyl is described in Bu Hoi et al., Rec Trav. Chim.,
68, 781, 1949; the compound of formula (II), in which X' is oxygen,
R'.sub.3 and R'.sub.4 are hydrogen and R'.sub.5 is p-methylphenyl
is described in Prevost et al., Compt. Rend. Acad. Sci., 258, 954,
1964; the compound of formula (II), in which X' is oxygen, R'.sub.3
and R'.sub.4 are hydrogen and R'.sub.5 is p-bromophenyl is
described in Nicolai et al., Eur. J. Med. Chem., 27, 977, 1992; the
compound of formula (II), in which X' is oxygen, R'.sub.4 and
R'.sub.5 are hydrogen and R'.sub.3 is 6-methyl is described in
Buchmann and Howton, J. Am. Chem. Soc., 68, 2718, 1946; the
compound of formula (II), in which X' is oxygen, R'.sub.4 and
R'.sub.5 are hydrogen and R'.sub.3 is 8-nitro is described in
Buchmann et al, J. Am Chem. Soc., 69, 380, 1947; the compound of
formula (II), in which X' is oxygen, R'.sub.4 is hydrogen, R'.sub.3
is 6-chloro, R'.sub.5 is p-chlorophenyl is described in Lutz et
al., J. Am. Chem. Soc., 68, 1813, 1946; the compound of formula
(II), in which X' is oxygen, R'.sub.3 and R'.sub.4 are hydrogen and
R'.sub.5 is 2-thiazolyl is described in Eur. Pat. Appl. EP 112,776;
compounds of formula (II), in which X' is oxygen, R'.sub.3 is
8-trifluoromethyl, R'.sub.4 is hydrogen and R'.sub.5 are phenyl, o-
and p-fluorophenyl, 3,4-dichlorophenyl, p-methoxyphenyl are
described in Nicolai et al., Eur. J. Med. Chem., 27, 977, 1992;
compounds of formula (II), in which X' is oxygen, R'.sub.3 is
6-bromo, R'.sub.4 is hydrogen and R'.sub.5 are phenyl or
p-fluorophenyl are described in Nicolai et al., Eur. J. Med. Chem.,
27, 977, 1992; other compounds of formula (II) are described in
Ger. Offen. DE 3,721,222 and in Eur. Pat. Appl. EP 384,313.
[0110] Compounds of formula (III), (IIId) and (IIIe) are
commercially available compounds or can be prepared from known
compounds by known methods (for example, compounds of formula (III)
in which R' is alkoxycarbonyl, R'.sub.1 and R'.sub.2 are hydrogen
and Ar' is as defined for the compounds of formula (I), are
described in Liebigs Ann. der Chemie, 523, 199, 1936).
[0111] The activity of the compounds of formula (A) as NK.sub.3
receptor antagonists in standard tests indicates that they are of
potential therapeutic utility in the treatment of Disorders herein
before referred to.
[0112] Accordingly, the present invention also provides a Salt of
the invention, or a pharmaceutically acceptablesolvate thereof, for
use as an active therapeutic substance.
[0113] The present invention further provides a pharmaceutical
composition comprising a Salt of the invention, or a
pharmaceutically acceptable solvate thereof, and a pharmaceutically
acceptable carrier.
[0114] The present invention also provides the use of a Salt of the
invention, or a pharmaceutically acceptable solvate thereof, in the
manufacture of a medicament for the treatment of the Primary.
Secondary or Further Disorders disclosed herein before.
[0115] Such a medicament and a composition of this invention, may
be prepared by admixture of a compound of the invention with an
appropriate carrier. It may contain a diluent, binder, filler,
disintegrant, flavouring agent, colouring agent, lubricant or
preservative in conventional manner.
[0116] These conventional excipients may be employed for example as
in the preparation of compositions of known agents for treating the
conditions.
[0117] Preferably, a pharmaceutical composition of the invention is
in unit dosage form and in a form adapted for use in the medical or
veterinarial fields. For example, such preparations may be in a
pack form accompanied by written or printed instructions for use as
an agent in the treatment of the conditions.
[0118] The suitable dosage range for the compounds of the invention
depends on the compound to be employed and on the condition of the
patient It will also depend, inter alia, upon the relation of
potency to absorbability and the frequency and route of
administration.
[0119] The compound or composition of the invention may be
formulated for administration by any route, and is preferably in
unit dosage form or in a form that a human patient may administer
to himself in a single dosage. Advantageously, the composition is
suitable for oral, rectal, topical, parenteral, intravenous or
intramuscular administration. Preparations may be designed to give
slow release of the active ingredient.
[0120] Compositions may, for example, be in the form of tablets,
capsules, sachets, vials, powders, granules, lozenges,
reconstitutable powders, or liquid preparations, for example
solutions or suspensions, or suppositories.
[0121] The compositions, for example those suitable for oral
administration, may contain conventional excipients such as binding
agents, for example syrup, acacia, gelatin, sorbitol, tragacanth,
or polyvinylpyrrolidone; fillers, for example lactose, sugar,
maize-starch, calcium phosphate, sorbitol or glycine; tabletting
lubricants, for example magnesium stearate; disintegrants, for
example starch, polyvinyl-pyrrolidone, sodium starch glycollate or
microcrystalline cellulose; or pharmaceutically acceptable setting
agents such as sodium lauryl sulphate.
[0122] Solid compositions may be obtained by conventional methods
of blending, filling. tabletting or the like. Repeated blending
operations may be used to distribute the active agent throughout
those compositions employing large quantities of fillers. When the
composition is in the form of a tablet, powder, or lozenge, any
carrier suitable for formulating solid pharmaceutical compositions
may be used, examples being magnesium stearate, starch, glucose,
lactose, sucrose, rice flour and chalk. Tablets may be coated
according to methods well known in normal pharmaceutical practice,
in particular with an enteric coating. The composition may also be
in the form of an ingestible capsule, for example of gelatin
containing the compound, if desired with a carrier or other
excipients.
[0123] Compositions for oral administration as liquids may be in
the form of, for example, emulsions, syrups, or elixirs, or may be
presented as a dry product for reconstitution with water or other
suitable vehicle before use. Such liquid compositions may contain
conventional additives such as suspending agents, for example
sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose,
carboxymethylcellulose, aluminium stearate gel, hydrogenated edible
fats; emulsifying agents, for example lecithin, sorbitan
monooleate, or acacia; aqueous or non-aqueous vehicles, which
include edible oils, for example almond oil, fractionated coconut
oil, oily esters, for example esters of glycerine, or propylene
glycol, or ethyl alcohol, glycerine, water or normal saline;
preservatives, for example methyl or propyl p-hydroxybenzoate or
sorbic acid; and if desired conventional flavouring or colouring
agents.
[0124] The compounds of this invention may also be administered by
a non-oral route. In accordance with routine pharmaceutical
procedure, the compositions may be formulated, for example for
rectal administration as a suppository. They may also be formulated
for presentation in an injectable form in an aqueous or non-aqueous
solution, suspension or emulsion in a pharmaceutically acceptable
liquid, e.g. sterile pyrogen-free water or a parenterally
acceptable oil or a mixture of liquids. The liquid may contain
bacteriostatic agents, anti-oxidants or other preservatives,
buffers or solutes to render the solution isotonic with the blood,
thickening agents, suspending agents or other pharmaceutically
acceptable additives. Such forms will be presented in unit dose
form such as ampoules or disposable injection devices or in
multi-dose forms such as a bottle from which the appropriate dose
may be withdrawn or a solid form or concentrate which can be used
to prepare an injectable formulation.
[0125] The compounds of this invention may also be administered by
inhalation, via the nasal or oral routes. Such administration can
be carried out with a spray formulation comprising a compound of
the invention and a suitable carrier, optionally suspended in, for
example, a hydrocarbon propellant.
[0126] Preferred spray formulations comprise micronised compound
particles in combination with a surfactant, solvent or a dispersing
agent to prevent the sedimentation of suspended particles.
Preferably, the compound particle size is from about 2 to 10
microns.
[0127] A further mode of administration of the compounds of the
invention comprises transdermal delivery utilising a skin-patch
formulation. A preferred formulation comprises a compound of the
invention dispersed in a pressure sensitive adhesive which adheres
to the skin, thereby permitting the compound to diffuse from the
adhesive through the skin for delivery to the patient. For a
constant rate of percutaneous absorption, pressure sensitive
adhesives known in the art such as natural rubber or silicone can
be used.
[0128] As mentioned above, the effective dose of compound depends
on the particular compound employed, the condition of the patient
and on the frequency and route of administration. A unit dose will
generally contain from 20 to 1000 mg and preferably will contain
from 30 to 500 mg. in particular 50, 100, 150, 200, 250, 300, 350,
400, 450, or 500 mgt. The composition may be administered once or
more times a day for example 2, 3 or 4 times daily, and the total
daily dose for a 70 ka adult will normally be in the range 100 to
3000 mg. Alternatively the unit dose will contain from 2 to 20 mg
of active ingredient and be administered in multiples, if desired,
to give the preceding daily dose.
[0129] No unacceptable toxicological effects are expected with
compounds of the invention when administered in accordance with the
invention.
[0130] The present invention also provides a method for the
treatment and/or prophylaxis of the Primary, Secondary or Further
Disorders in mammals, particularly humans, which comprises
administering to the mammal in need of such treatment and/or
prophylaxis an effective, non-toxic pharmceutically acceptable
amount of a Salt of the invention or a pharmaceutically acceptable
solvate thereof.
[0131] The activity of the compounds of the present invention, as
NK.sub.3 ligands, is determined by their ability to inhibit the
binding of the radiolabelled NK.sub.3 ligands,
[.sup.125I]-[Me-Phe.sup.7]-NKB or [.sup.3H]-Senktide, to guinea-pig
and human NK.sub.3 receptors (Renzetti et al., 1991, Neuropeptide,
18, 104-114; Buell et al, 1992, FEBS, 299(1), 90-95; Chung et a,
1994, Biochem. Biophys. Res. Commun., 198(3), 967-972).
[0132] The bindings assays utilized allow the determination of the
concentration of the individual compound required to reduce by 50%
the [.sup.125I]-[Me-Phe.sup.7]-NKB and [.sup.3H]-Senktide specific
binding to NK.sub.3 receptor in equilibrium conditions (IC50).
[0133] Binding assays provide for each compound tested a mean
IC.sub.50 value of 2-5 separate experiments performed in duplicate
or triplicate. The most potent compounds of the present invention
show IC.sub.50 values in the range 1-1000 nM; in particular, in
guinea-pig cortex membranes by displacement of [.sup.3H]-Senktide,
the compound of the Example 1 displays a K.sub.i of 4.8 nM (n=3).
The NK.sub.3-antagonist activity of the compounds of the present
invention is determined by their ability to inhibit
senktide-induced contraction of the guinea-pig ileum (Maggi et al,
1990, Br. J. Pharmacol., 101, 996-1000) and rabbit isolated iris
sphincter muscle (Hall et al., 1991, Eur. J. Pharmacol., 199, 9-14)
and human NK.sub.3 receptors-mediated Ca.sup.++ mobilization
(Mochizuki et al, 1994, J. Biol. Chem., 269, 9651-9658). Guinea-pig
and rabbit in-vitro functional assays provide for each compound
tested a mean K.sub.B value of 3-8 separate experiments, where
K.sub.B is the concentration of the individual compound required to
produce a 2-fold rightward shift in the concentration-response
curve of senktide. Human receptor functional assay allows the
determination of the concentration of the individual compound
required to reduce by 50% (IC.sub.50 values) the Ca.sup.++
mobilization induced by the agonist NKB. In this assay, the
compounds of the present invention behave as antagonists.
[0134] The therapeutic potential of the compounds of the present
invention in treating the conditions can be assessed using rodent
disease models.
[0135] The following Description illustrates the preparation of an
intermediate, whereas the Example illustrates the preparation of a
compound of the present invention but they do not limit the
invention in any way.
Experimental Details
[0136] DESCRIPTION 1:
[0137]
(S)-(-)-N-(.alpha.-ethylbenzyl)-3-hydroxy-2phenyl-4-quinoline
carboxamide
[0138] 2.49 g (9.4 mmols) of 3-hydroxy-2-phenyl-4-quinoline
carboxylic acid (CAS [485-89-2]) were suspended in 150 ml of a
mixture of THF/MeCN 7:3, respectively; 1.40 g (10.3 mmols) of
1-hydroxybenzotriazole (HOBT) were added to the suspension and then
1.27 g (9.4 mmols) of (S)-(-)-1-phenylpropylamine, dissolved in 20
ml of methylene chloride were added dropwise over 10 minutes
period. The reaction mixture was stirred at room temperature for 30
minutes and then 2.13 g (10.3 mmols) of dicyclohexylcarbodiimide
(DCC), dissolved in 20 ml of methylene chloride, were added
dropwise and the reaction stirred overnight. 20 ml of H.sub.2O were
added and the reaction stirred 30 minutes, then the solvent was
evaporated in vacuo to dryness. The residue was taken up in EtOAc,
the precipitated dicyclohexylurea (DCU) was filtered off and the
filtrate washed with water, 20% citric acid, 5% NaHCO.sub.3, brine
and the organic layer dried over Na.sub.2SO.sub.4 and the solvent
evaporated in vacuo. The residue was purified by silica-gel (60-240
mesh) flash column chromatography, eluting with a mixture of
hexane/EtOAc 9:1, containing increasing amounts of EtOAc, until the
ratio 7:3. The purified product was crystallized from i-PrOH to
yield 1.75 g of the title compound as a white solid.
[0139] C.sub.25H.sub.22N.sub.2O.sub.2
[0140] M.P.=168-168.4.degree. C.
[0141] M.W.=382.47
[0142] [.alpha.].sub.D.sup.20=-28.5 (c=0.5, MeOH)
[0143] Elemental analysis: Calcd. C, 78.51; H, 5.80; N, 7.33; Found
C. 78.49; H, 5.84; N, 7.86.
[0144] I.R. (Kbr): 3370; 1625; 1525 cm-1.
[0145] 300 MHz .sup.1H-NMR (DMSO-.sub.6): .delta.: 9.80(s, 1H);
9.11 (d, 1H); 8.00-7.94 (m, 3H); 7.61-7.42 (m, 8H); 7.38 (dd, 2H);
7.28 (dd, 1H); 5.06 (dt, 1H); 1.82 (ddq, 2H); 0.97 (t, 3H).
[0146] MS (EI; TSQ 700; source 200.degree. C.; 70 eV; 200 .mu.A):
382 (M+.); 264; 247; 219.
EXAMPLE 1
(S)-(+)-N-(.alpha.-ethylbenzyl)-3-hydroxy-2-phenyl-4-quinoline
Carboxamide Sodium Salt Sesquihydrate
[0147] 500 mg, (1.31 mmols) of
(S)-(-)-N-(.alpha.-ethylbenzyl)-3-hydroxy-2- -phenyl-4-quinoline
carboxamide (the compound of Description 1, dissolved in 20 ml of
MeOH containing 1.31 ml of 1N NaOH (1.31 mmols), were stirred at
40.degree. C. for 30 minutes and then the solvent was evaporated in
vacuo to dryness. Crystallization of the residue from a mixture of
toluene and iPrOH yielded 240 m; of the title compound as a yellow
solid.
[0148] C.sub.25H.sub.21N.sub.2O.sub.2Na 1.5 H.sub.2O
[0149] M.P.=110.degree. C. (dec.)
[0150] M.W.=431.48
[0151] [.alpha.].sub.s.sup.20 =+169.81 (c=0.5, MeOH)
[0152] Elemental analysis: Calcd. C, 69.59; H, 5.61; N, 6.49; Na,
5.33 Found C, 69.07; H, 5.45; N, 6.05; Na, 5.49.
[0153] I.R. (nujol): 1640; 1460; 1380 cm-1.
[0154] 300 MHz .sup.1H-NMR (DMSO- d.sub.6): .delta.: 13.3 (d, 1H);
9.4 (d, 1H); 8.23 (d, 2H); 7.60 (dd, 1H); 7.41-7.09 (m, 9H); 6.09
(ddd, 1H); 5.08 (dt, 1H); 1.80 (m, 2H); 0.91 (t, 3H).
* * * * *