U.S. patent application number 16/250278 was filed with the patent office on 2019-05-16 for ethynyl derivatives.
This patent application is currently assigned to Hoffmann-La Roche Inc.. The applicant listed for this patent is Hoffmann-La Roche Inc.. Invention is credited to BARBARA BIEMANS, GEORG JAESCHKE, FIONN O'HARA, ANTONIO RICCI, DANIEL RUEHER.
Application Number | 20190144458 16/250278 |
Document ID | / |
Family ID | 56418435 |
Filed Date | 2019-05-16 |
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United States Patent
Application |
20190144458 |
Kind Code |
A1 |
BIEMANS; BARBARA ; et
al. |
May 16, 2019 |
ETHYNYL DERIVATIVES
Abstract
The present invention relates to compounds that may be used in
the treatment of Parkinson's disease, anxiety, emesis, obsessive
compulsive disorder, autism, neuroprotection, cancer, depression or
diabetes type 2.
Inventors: |
BIEMANS; BARBARA; (Basel,
CH) ; JAESCHKE; GEORG; (Basel, CH) ; RICCI;
ANTONIO; (Birsfelden, CH) ; RUEHER; DANIEL;
(Raedersdorf, FR) ; O'HARA; FIONN; (Basel,
CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Hoffmann-La Roche Inc. |
Little Falls |
NJ |
US |
|
|
Assignee: |
Hoffmann-La Roche Inc.
Little Falls
NJ
|
Family ID: |
56418435 |
Appl. No.: |
16/250278 |
Filed: |
January 17, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
PCT/EP2017/067495 |
Jul 12, 2017 |
|
|
|
16250278 |
|
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Current U.S.
Class: |
514/274 |
Current CPC
Class: |
A61P 3/10 20180101; A61P
1/08 20180101; C07B 2200/09 20130101; C07D 487/10 20130101; A61P
25/22 20180101; A61P 35/00 20180101; A61P 25/24 20180101; A61P
25/00 20180101; C07B 2200/07 20130101; A61P 39/00 20180101; A61P
25/16 20180101 |
International
Class: |
C07D 487/10 20060101
C07D487/10 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 18, 2016 |
EP |
16179837.6 |
Claims
1. A compound of formula IA or IB ##STR00010## or a
pharmaceutically acceptable salt or acid addition salt, a racemic
mixture, or its corresponding enantiomer and/or optical isomer
and/or stereoisomer thereof.
2. A process for the manufacture of the compound of formula IA or
IB as defined in claim 1, which process comprises alkylating a
compound of formula ##STR00011## with ethyliodide and separating of
the isomers to a compound of formulas ##STR00012## or, if desired,
converting the compound obtained into a pharmaceutically acceptable
salt thereof.
3. A pharmaceutical composition comprising a compound of formula IA
or IB as in claim 1 and a pharmaceutically acceptable
excipient.
4. A method for the treatment of Parkinson's disease, anxiety,
emesis, obsessive compulsive disorder, autism, neuroprotection,
cancer, depression and diabetes type 2 in a mammal, which method
comprises administering an effective amount of a compound of
formula IA or IB as in claim 1 to the mammal in need thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of International
Application PCT/EP2017/067495, filed Jul. 12, 2017, which claims
benefit of priority to European Application 16179837.6, filed Jul.
18, 2016, each of which is incorporated herein by reference in its
entirety.
[0002] The present invention relates to compounds of formulas IA
and IB
##STR00001##
or to a pharmaceutically acceptable salt or acid addition salt, to
a racemic mixture, or to its corresponding enantiomer and/or
optical isomer and/or stereoisomer thereof.
[0003] It has been surprisingly found that the compounds of
formulas IA and IB are positive allosteric modulators (PAMs) of
metabotropic glutamate receptor 4 (mGluR4). Metabotropic glutamate
receptor 4 is a protein that in humans is encoded by the GRM4
gene.
[0004] Together with GRM6, GRM7 and GRM8 it belongs to group III of
the Metabotropic glutamate receptor family, and is negatively
coupled to adenylate cyclase via activation of the G.alpha.i/o
protein. It is expressed primarily on presynaptic terminals,
functioning as an autoreceptor or heteroceptor and its activation
leads to decreases in transmitter release from presynaptic
terminals. mGluR4 is currently receiving much attention based
primarily upon its unique distribution and the recent evidence that
activation of this receptor plays key modulatory role in many CNS
and non-CNS pathways (Celanire S, Campo B, Expert Opinion in Drug
Discovery, 2012)
[0005] The similarity in the ligand binding domains of group III
mGluR's creates a challenge for identifying selective orthosteric
agonists of this receptor, although some progress has been made in
this area. However, targeting positive allosteric modulators (PAMs)
rather than orthosteric agonists provides a broader opportunity to
identify molecules that are exclusively selective between
mGluRs.
[0006] mGluR4 PAMs are emerging as promising therapeutic agents for
the treatment of motor (and non-motor) symptoms as well as a
disease-modifying agent in Parkinson's disease through a
non-dopaminergic approach.
[0007] Parkinson's disease is a progressive neurodegenerative
disease that results in the loss of dopaminergic neurons in the
substantia nigra (SN). One consequence of the depletion of dopamine
in this disease is a series of movement disorders, including
bradykinesia, akinesia, tremor, gait disorders and problems with
balance. These motor disturbances form the hallmark of PD, although
there are many other non-motor symptoms that are associated with
the disease. Early in the course of the disease, PD symptoms are
effectively treated by dopamine replacement or augmentation, with
the use of dopamine D2 receptor agonists, levodopa or monoamine
oxidase B inhibitors. However, as the disease progresses these
agents become less effective in controlling motor symptoms.
Additionally, their use is limited by the emergence of adverse
effects including dopamine agonist-induced dyskinesias.
[0008] Consequently, there remains a need for new approaches to the
treatment of PD that improve the effectiveness of the control of
motor symptoms.
[0009] Activation of metabotropic glutamate receptor 4 (mGluR4) has
been proposed as a potential therapeutic approach to Parkinson's
disease. A member of the group III mGluRs, mGluR4 is predominantly
a presynaptic glutamate receptor that is expressed in several key
locations in the basal ganglia circuits that control movement.
Activation of mGluR4 with group III-preferring agonists decreases
inhibitory and excitatory post synaptic potentials, presumably by
decreasing the release of GABA and glutamate respectively.
[0010] The search for novel drugs that relieve motor symptoms of
Parkinsonism whilst attenuating the ongoing degeneration of
nigrostriatal neurons is of particular interest. Orthosteric mGluR4
agonist L-AP4 has demonstrated neuroprotective effects in a 6-OHDA
rodent model of PD and first positive allosteric modulator
(-)-PHCCC reduced nigrostriatal degeneration in mice treated with
1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP). These studies
provide convincing preclinical evidence suggesting that mGluR4
activators constitute a valid approach not only for symptomatic
treatments of PD, but also potentially as disease modifiers for
this indication.
[0011] The neuroprotective effects of selective mGluR4 modulators
was also described in Neuroreport, 19(4), 475-8, 2008, Proc. Natl.
Acad. Sci, USA, 100(23), 13668-73, 2003 and J. Neurosci. 26(27),
7222-9, 2006 and Mol. Pharmacol. 74(5), 1345-58, 2008.
[0012] Anxiety disorders are among the most prevalent psychiatric
disorders in the world, and are co-morbid with Parkinson's disease
(Prediger R, et al. Neuropharmacology 2012; 62:115-24). Excessive
glutamatergic neurotransmission is one important feature of anxiety
pathophysiology. Based on presynaptic localization of mGluR4 in
brain areas involved in anxiety and mood disorders, and dampening
excessive brain excitability, the mGluR4 activators may represent a
new generation of anxiolytic therapeutics (Eur. J. Pharmacol.,
498(1-3), 153-6, 2004).
[0013] Addex has reported in 2010 that ADX88178 was active in two
preclinical rodent models of anxiety: the marble burying test in
mice and EPM in mice and rats. ADX88178 also displayed an
anxiolytic-like profile in the rat EPM test after oral dosing.
[0014] mGluR4 modulators were also shown to exert anti-depressive
actions (Neuropharmacology, 46(2), 151-9, 2004).
[0015] In addition, mGluR4 modulators were also shown to be
involved in glucagon secretion inhibition (Diabetes, 53(4),
998-1006, 2004). Therefore, orthosteric or positive allosteric
modulators of mGluR4 have potential for the treatment of type 2
diabetes through its hypoglycemic effect.
[0016] Moreover, mGluR4 was shown to be expressed in prostate
cancer cell-line (Anticancer Res. 29(1), 371-7, 2009) or colorectal
carcinoma (Cli. Cancer Research, 11(9)3288-95, 2005). mGluR4
modulators may therefore have also potential role for the treatment
of cancers.
[0017] Other proposed effects of mGluR4 PAM's can be expected for
the treatment of emesis, obsessive compulsive disorder, anorexia
and autism.
[0018] Compounds of formulas IA and IB are distinguished by having
valuable therapeutic properties. They can be used in the treatment
or prevention of disorders, relating to allosteric modulators for
the mGluR4 receptor.
[0019] The most preferred indications for compounds which are
allosteric modulators for the mGluR4 receptor are Parkinson's
disease, anxiety, emesis, obsessive compulsive disorder, anorexia,
autism, neuroprotection, cancer, depression and type 2
diabetes.
[0020] The present invention relates to compounds of formulas IA
and IB and to their pharmaceutically acceptable salts, to these
compounds as pharmaceutically active substances, to the processes
for their production as well as to their use in the treatment or
prevention of disorders, relating to allosteric modulators for the
mGluR4 receptor, such as Parkinson's disease, anxiety, emesis,
obsessive compulsive disorder, autism, neuroprotection, cancer,
depression and diabetes type 2 and to pharmaceutical compositions
containing the compounds of formula IA and IB.
[0021] A further object of the present invention is a method for
the treatment or prophylaxis of Parkinson's disease, anxiety,
emesis, obsessive compulsive disorder, anorexia, autism,
neuroprotection, cancer, depression and type 2 diabetes, which
method comprises administering an effective amount of a compound of
formulas IA and IB to a mammal in need.
[0022] Furthermore, the invention includes all racemic mixtures,
all their corresponding enantiomers and/or optical isomers, or
analogues containing isotopes of hydrogen, fluorine, carbon, oxygen
or nitrogen.
[0023] The term "pharmaceutically acceptable acid addition salt"
embraces a salt with inorganic and organic acids, such as
hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid,
citric acid, formic acid, fumaric acid, maleic acid, acetic acid,
succinic acid, tartaric acid, methane-sulfonic acid or
p-toluenesulfonic acid.
[0024] The preparation of compounds of formulas IA and IB of the
present invention may be carried out in sequential or convergent
synthetic routes. Syntheses of the compounds of the invention are
shown in the following scheme 1. The skills required for carrying
out the reaction and purification of the resulting products are
known to those skilled in the art. The substituents and indices
used in the following description of the processes have the
significance given herein before.
[0025] The compounds of formulas IA and IB can be manufactured by
the methods given below, by the methods given in the examples or by
analogous methods. Appropriate reaction conditions for the
individual reaction steps are known to a person skilled in the art.
The reaction sequence is not limited to the one displayed in the
schemes, however, depending on the starting materials and their
respective reactivity the sequence of reaction steps can be freely
altered. Starting materials are either commercially available or
can be prepared by methods analogous to the methods given below, by
methods described in references cited in the description or in the
examples, or by methods known in the art.
[0026] The present compounds of formulas IA and IB and their
pharmaceutically acceptable salts may be prepared by methods, known
in the art, for example by the process variant described below
which process comprises [0027] alkylating a compound of formula
##STR00002##
[0028] with ethyliodide and separating of the isomers to a compound
of formulas
##STR00003##
[0029] or, if desired, converting the compounds obtained into
pharmaceutically acceptable salts thereof.
[0030] The preparation of compounds of formulas IA and IB is
further described in more detail in scheme 1 and in examples
1-2.
##STR00004## ##STR00005##
[0031] Compounds of general formula I can be obtained for example
by reacting 2,6-difluoro-4-iodo-phenylamine 6 with the
appropriately synthesized aminoester of formula 5 with CDI in a
solvent such as DMF to form the desired urea analogue of formula 7.
Ring closure of 7 with a strong base such as NaH and introduction
of methyl via alkylation of protected pyrazole 8 forms the desired
alkylated compound 9. Sonogashira coupling of 9 with
phenylacetylene 10 forms after deprotection of the SEM group the
desired ethynyl compound 12. Introduction of ethyl via alkylation
and separation of the formed isomers yield the desired final
compounds of formula I (scheme 1).
[0032] Generally speaking, the sequence of steps used to synthesize
the compound of formula I can also be modified in certain
cases.
Biological Assay and Data
[0033] Determination of EC.sub.50 Values Using a Ca2+ Mobilization
In Vitro Assay on Recombinant Human mGlu4 Expressed in HEK293
Cells:
[0034] A monoclonal HEK-293 cell line stably transfected with a
cDNA encoding for the human mGlu4 receptor was generated; for the
work with mGlu4 Positive Allosteric Modulators (PAMs), a cell line
with low receptor expression levels and low constitutive receptor
activity was selected to allow the differentiation of agonistic
versus PAM activity. Cells were cultured according to standard
protocols (Freshney, 2000) in Dulbecco's Modified Eagle Medium with
high glucose supplemented with 1 mM glutamine, 10% (vol/vol)
heat-inactivated bovine calf serum, Penicillin/Streptomycin, 50
.mu.g/ml hygromycin and 15 .mu.g/ml blasticidin (all cell culture
reagents and antibiotics from Invitrogen, Basel, Switzerland).
[0035] About 24 hrs before an experiment, 5.times.10.sup.4
cells/well were seeded in poly-D-lysine coated,
black/clear-bottomed 96-well plates. The cells were loaded with 2.5
.mu.M Fluo-4AM in loading buffer (1.times.HBSS, 20 mM HEPES) for 1
hr at 37.degree. C. and washed five times with loading buffer. The
cells were transferred into a Functional Drug Screening System 7000
(Hamamatsu, Paris, France), and 11 half logarithmic serial
dilutions of test compound at 37.degree. C. were added and the
cells were incubated for 10-30 min. with on-line recording of
fluorescence. Following this pre-incubation step, the agonist
(2S)-2-amino-4-phosphonobutanoic acid (L-AP4) was added to the
cells at a concentration corresponding to EC.sub.20 with on-line
recording of fluorescence; in order to account for day-to-day
variations in the responsiveness of cells, the EC.sub.20 of L-AP4
was determined immediately ahead of each experiment by recording of
a full dose-response curve of L-AP4.
[0036] Responses were measured as peak increase in fluorescence
minus basal (i.e. fluorescence without addition of L-AP4),
normalized to the maximal stimulatory effect obtained with
saturating concentrations of L-AP4. Graphs were plotted with the %
maximal stimulatory using XLfit, a curve fitting program that
iteratively plots the data using Levenburg Marquardt algorithm. The
single site competition analysis equation used was
y=A+((B-A)/(1+((x/C)D))), where y is the % maximal stimulatory
effect, A is the minimum y, B is the maximum y, C is the EC.sub.50,
x is the log 10 of the concentration of the competing compound and
D is the slope of the curve (the Hill Coefficient). From these
curves the EC.sub.50 (drug concentration at which 50% of the
maximal receptor activation was achieved), the Hill coefficient as
well as the maximal response in % of the maximal stimulatory effect
obtained with saturating concentrations of L-AP4 were calculated
(see FIG. 1).
[0037] Positive signals obtained during the pre-incubation with the
PAM test compounds (i.e. before application of an EC.sub.20
concentration of L-AP4) were indicative of an agonistic activity,
the absence of such signals were demonstrating the lack of
agonistic activities. A depression of the signal observed after
addition of the EC.sub.20 concentration of L-AP4 was indicative of
an inhibitory activity of the test compound.
BRIEF DESCRIPTION OF THE FIGURE
[0038] FIG. 1: Illustration of the experimental outline for mGlu4
PAM Ca2+ mobilization screening assay and the determination of
EC.sub.50 and % Emax values.
LIST OF EXAMPLES AND DATA
TABLE-US-00001 [0039] EC.sub.50 (nM) mGlu4 Eff. Structure Name PAM
(%) 1 ##STR00006## (4S)-3'-[2,6-Difluoro-4-(2-
phenylethynyl)phenyl]-2-ethyl- 1'-methyl-spiro[6,7-dihydro-
5H-indazole-4,6'- hexahydropyrimidine]-2',4'- dione 77 132 2
##STR00007## (4S)-3'-[2,6-Difluoro-4-(2-
phenylethynyl)phenyl]-1-ethyl- 1'-methyl-spiro[6,7-dihydro-
5H-indazole-4,6'- hexahydropyrimidine]-2',4'- dione 85 136
[0040] The compounds of formulas IA and IB and pharmaceutically
acceptable salts thereof can be used as medicaments, e.g. in the
form of pharmaceutical preparations. The pharmaceutical
preparations can be administered orally, e.g. in the form of
tablets, coated tablets, dragees, hard and soft gelatine capsules,
solutions, emulsions or suspensions. However, the administration
can also be effected rectally, e.g. in the form of suppositories,
or parenterally, e.g. in the form of injection solutions.
[0041] The compounds of formulas IA and IB and pharmaceutically
acceptable salts thereof can be processed with pharmaceutically
inert, inorganic or organic carriers for the production of
pharmaceutical preparations. Lactose, corn starch or derivatives
thereof, talc, stearic acid or its salts and the like can be used,
for example, as such carriers for tablets, coated tablets, dragees
and hard gelatin capsules. Suitable carriers for soft gelatin
capsules are, for example, vegetable oils, waxes, fats, semi-solid
and liquid polyols and the like; depending on the nature of the
active substance no carriers are, however, usually required in the
case of soft gelatin capsules. Suitable carriers for the production
of solutions and syrups are, for example, water, polyols, sucrose,
invert sugar, glucose and the like. Adjuvants, such as alcohols,
polyols, glycerol, vegetable oils and the like, can be used for
aqueous injection solutions of water-soluble salts of compounds of
formula IA and IB, but as a rule are not necessary. Suitable
carriers for suppositories are, for example, natural or hardened
oils, waxes, fats, semi-liquid or liquid polyols and the like.
[0042] In addition, the pharmaceutical preparations can contain
preservatives, solubilizers, stabilizers, wetting agents,
emulsifiers, sweeteners, colorants, flavorants, salts for varying
the osmotic pressure, buffers, masking agents or antioxidants. They
can also contain still other therapeutically valuable
substances.
[0043] As mentioned earlier, medicaments containing a compound of
formulas IA and IB or pharmaceutically acceptable salts thereof and
a therapeutically inert excipient are also an object of the present
invention, as is a process for the production of such medicaments
which comprises bringing one or more compounds of formula IA and IB
or pharmaceutically acceptable salts thereof and, if desired, one
or more other therapeutically valuable substances into a galenical
dosage form together with one or more therapeutically inert
carriers.
[0044] As further mentioned earlier, the use of the compounds of
formulas IA and IB for the preparation of medicaments useful in the
prevention and/or the treatment of the above recited diseases is
also an object of the present invention.
[0045] The dosage can vary within wide limits and will, of course,
be fitted to the individual requirements in each particular case.
In general, the effective dosage for oral or parenteral
administration is between 0.01-20 mg/kg/day, with a dosage of
0.1-10 mg/kg/day being preferred for all of the indications
described. The daily dosage for an adult human being weighing 70 kg
accordingly lies between 0.7-1400 mg per day, preferably between 7
and 700 mg per day.
Preparation of Pharmaceutical Compositions Comprising Compounds of
the Invention
[0046] Tablets of the following composition are manufactured in the
usual manner:
TABLE-US-00002 mg/tablet ingredient 5 25 100 500 Compounds of
formula IA or IB 5 25 100 500 Lactose Anhydrous DTG 125 105 30 150
Sta-Rx 1500 6 6 6 60 Microcrystalline Cellulose 30 30 30 450
Magnesium Stearate 1 1 1 1 Total 167 167 167 831
[0047] Manufacturing Procedure [0048] 1. Mix ingredients 1, 2, 3
and 4 and granulate with purified water. [0049] 2. Dry the granules
at 50.degree. C. [0050] 3. Pass the granules through suitable
milling equipment. [0051] 4. Add ingredient 5 and mix for three
minutes; compress on a suitable press.
[0052] Capsules of the following composition are manufactured:
TABLE-US-00003 mg/capsule ingredient 5 25 100 500 Compound of
formula IA or IB 5 25 100 500 Hydrous Lactose 159 123 148 -- Corn
Starch 25 35 40 70 Talk 10 15 10 25 Magnesium Stearate 1 2 2 5
Total 200 200 300 600
[0053] Manufacturing Procedure [0054] 1. Mix ingredients 1, 2 and 3
in a suitable mixer for 30 minutes. [0055] 2. Add ingredients 4 and
5 and mix for 3 minutes. [0056] 3. Fill into a suitable
capsule.
[0057] A compound of formula IA or IB, lactose and corn starch are
firstly mixed in a mixer and then in a comminuting machine. The
mixture is returned to the mixer; the talc is added thereto and
mixed thoroughly. The mixture is filled by machine into suitable
capsules, e.g. hard gelatin capsules.
[0058] Injection solutions of the following composition are
manufactured:
TABLE-US-00004 ingredient mg/injection solution. Compound of
formula IA or IB 3 Polyethylene Glycol 400 150 acetic acid q.s. ad
pH 5.0 water for injection solutions ad 1.0 ml
[0059] Manufacturing Procedure
[0060] A compound of formula IA or IB is dissolved in a mixture of
Polyethylene Glycol 400 and water for injection (part). The pH is
adjusted to 5.0 by acetic acid. The volume is adjusted to 1.0 ml by
addition of the residual amount of water. The solution is filtered,
filled into vials using an appropriate overage and sterilized.
EXPERIMENTAL SECTION
Example 1
(4S)-3'-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-2-ethyl-1'-methyl-spiro[6-
,7-dihydro-5H-indazole-4,6'-hexahydropyrimidine]-2',4'-dione
##STR00008##
[0061] Step 1:
2-((2-(Trimethylsilyl)ethoxy)methyl)-6,7-dihydro-2H-indazol-4(5H)-one
[0062] 6,7-Dihydro-2H-indazol-4(5H)-one (CAS 912259-10-0) (1.46 g,
10.7 mmol) was dissolved in THF (15 ml) and cooled to 0-5.degree.
C. Sodium hydride (60% dispersion in mineral oil) (450 mg, 11.3
mmol, 1.05 equiv.) was added carefully in portions and the mixture
was stirred for 60 minutes at room temperature. The reaction
mixture was cooled again to 0-5.degree. C. and
(2-(chloromethoxy)ethyl)trimethylsilane (2.28 ml, 2.15 g, 12.9
mmol, 1.2 equiv.) was added and the mixture was stirred for 2 hours
at room temperature. The reaction mixture was extracted carefully
with saturated NaHCO.sub.3 solution and twice with ethyl acetate.
The organic layers were washed with brine, dried over sodium
sulfate and evaporated to dryness. The desired
2-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-2H-indazol-4(5H)-one
(quant. yield) was obtained as a yellow oil, MS: m/e=267.2
(M+H.sup.+).
Step 2:
(NE)-2-Methyl-N-[1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-5H-i-
ndazol-4-ylidene]propane-2-sulfinamide
[0063]
2-((2-(Trimethylsilyl)ethoxy)methyl)-6,7-dihydro-2H-indazol-4(5H)-o-
ne (Example 1, step 1) (40 g, 150.14 mmol) was dissolved in 400 ml
of THF. (R)-2-Methylpropane-2-sulfinamide (CAS 196929-78-9) (27.3
g, 225.2 mmol, 1.5 equiv.) and titanium(IV) ethoxide (102.75 g,
93.4 ml, 450.42 mmol, 3.0 equiv.) were added and the mixture was
stirred for 4 hours at 70.degree. C. The reaction mixture was
cooled and saturated NaHCO.sub.3 solution and ethyl acetate were
added. The formed suspension was filtered through celite and the
filtrate was extracted twice with ethyl acetate. The organic layers
were washed brine, dried over sodium sulfate and evaporated to
dryness. The desired
(NE)-2-methyl-N-[1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-5H-indazol--
4-ylidene]propane-2-sulfinamide (20.0 g, 36% yield) was obtained as
a brown oil, MS: m/e=370.2 (M+H.sup.+).
Step 3: Methyl
2-[(4S)-4-[[(R)-tert-butylsulfinyl]amino]-1-(2-trimethylsilylethoxymethyl-
)-6,7-dihydro-5H-indazol-4-yl]acetate
[0064] Methyl acetate (22.25 g, 23.9 ml, 300.3 mmol, 3 equiv.) was
dissolved in 370 ml of dry THF and the solution was cooled to
-70.degree. C. LDA (2.0 M in THF/heptane/ethylbenzene) (150 ml,
300.3 mmol, 3 equiv.) was added drop wise at -75.degree. C. to
-65.degree. C. and the mixture was stirred for 45 minutes at
-70.degree. C. Chlorotitanium triisopropoxide (1.0 M in
dichloromethane) (400 ml, 400 mmol, 4 equiv.) was added drop wise
at -75.degree. C. to -65.degree. C. and the mixture was stirred for
45 minutes at -70.degree. C.
(NE)-2-methyl-N-[1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-5H-indazol--
4-ylidene]propane-2-sulfinamide (Example 1, step 2) (37 g, 100
mmol) dissolved in 370 ml of dry THF was added drop wise at
-75.degree. C. to -65.degree. C. and the mixture was stirred for 1
hour at -70.degree. C. Saturated NaHCO.sub.3 solution was added and
the mixture stirred for 10 minutes. Ethyl acetate was added to the
formed suspension and the mixture was stirred for 10 minutes. The
formed suspension was filtered through celite and the filtrate was
extracted twice with ethyl acetate. The organic layers were washed
with water and brine, dried over sodium sulfate and evaporated to
dryness. The crude product was purified by flash chromatography.
The desired methyl
2-[(4S)-4-[[(R)-tert-butylsulfinyl]amino]-1-(2-trimethylsilylethoxymethyl-
)-6,7-dihydro-5H-indazol-4-yl]acetate (22 g, 40% yield) was
obtained as a brown oil, MS: m/e=444.2 (M+H.sup.+).
Step 4: Methyl
2-[(4S)-4-amino-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-5H-indazol-4-
-yl]acetate
[0065] Methyl
2-[(4S)-4-[[(R)-tert-butylsulfinyl]amino]-1-(2-trimethylsilylethoxymethyl-
)-6,7-dihydro-5H-indazol-4-yl]acetate (Example 1, step 3) (20 g,
45.08 mmol) was dissolved in 500 ml of ethyl acetate and HCl (4N in
ethyl acetate) (56.3 ml, 225.4 mmol, 5 equiv.) was added drop wise
at 0-5.degree. C. The mixture was stirred for 30 minutes at
0-5.degree. C. The reaction mixture was evaporated at 0-5.degree.
C. and extracted with saturated NaHCO.sub.3 solution and three
times with dichloromethane. The organic layers were combined, dried
over sodium sulfate and evaporated to dryness. The desired methyl
2-[(4
S)-4-amino-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-5H-indazol-4-yl]a-
cetate (340 mg, 54% yield) was obtained as a yellow oil, MS:
m/e=340.1 (M+H.sup.+).
Step 5: Methyl
2-[(4S)-4-[(2,6-difluoro-4-iodo-phenyl)carbamoylamino]-1-(2-trimethylsily-
lethoxymethyl)-6,7-dihydro-5H-indazol-4-yl]acetate
[0066] 2,6-Difluoro-4-iodoaniline (14.4 g, 56.56 mmol, 1.2 equiv.)
was dissolved in DMF (250 ml) and CDI (9.17 g, 56.56 mmol, 1.2
equiv.) was added at room temperature. The mixture was stirred for
1 hour at 100.degree. C. To the mixture methyl
2-[(4S)-4-amino-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-5H-indazol-4-
-yl]acetate (Example 1, step 4) (16 g, 47.13 mmol, 1.0 equiv.)
dissolved in 20 ml of DMF was added at room temperature and the
mixture was stirred for 2 hours at room temperature. The reaction
mixture was poured into water and extracted three times with ethyl
acetate. The organic layers were washed with water and brine, dried
over sodium sulfate and evaporated to dryness. The crude product
was purified by flash chromatography. The desired methyl
2-[(4S)-4-[(2,6-difluoro-4-iodo-phenyl)carbamoylamino]-1-(2-trimethylsily-
lethoxymethyl)-6,7-dihydro-5H-indazol-4-yl]acetate (9.1 g, 19%
yield) was obtained as a brown gum, MS: m/e=621.1 (M+H.sup.+).
Step 6:
(4S)-3'-(2,6-Difluoro-4-iodo-phenyl)-1-(2-trimethylsilylethoxymeth-
yl)spiro[6,7-dihydro-5H-indazole-4,6'-hexahydropyrimidine]-2',4'-dione
[0067] (18 g, 29.01 mmol) Methyl
2-[(4S)-4-[(2,6-difluoro-4-iodo-phenyl)carbamoylamino]-1-(2-trimethylsily-
lethoxymethyl)-6,7-dihydro-5H-indazol-4-yl]acetate (Example 1, step
5) was dissolved in THF (360 ml) and sodium hydride (60% in mineral
oil) (1.74 g, 43.52 mmol, 1.5 equiv.) was added at 0-5.degree. C.
The mixture was stirred for 1 hour at room temperature. The
reaction mixture was extracted with saturated NH.sub.4Cl solution
and three times with ethyl acetate. The organic layers were washed
with brine, dried over sodium sulfate and evaporated to dryness.
The desired
(4S)-3'-(2,6-difluoro-4-iodo-phenyl)-1-(2-trimethylsilylethoxymethyl)spir-
o[6,7-dihydro-5H-indazole-4,6'-hexahydropyrimidine]-2',4'-dione
(240 mg, 86% yield) was obtained as a yellow gum, MS: m/e=589.0
(M+H.sup.+).
Step 7: (4
S)-3'-(2,6-Difluoro-4-iodo-phenyl)-1'-methyl-1-(2-trimethylsily-
lethoxymethyl)spiro[6,7-dihydro-5H-indazole-4,6'-hexahydropyrimidine]-2',4-
'-dione
[0068] (17 g, 28.9 mmol)
(4S)-3'-(2,6-Difluoro-4-iodo-phenyl)-1-(2-trimethylsilylethoxymethyl)spir-
o[6,7-dihydro-5H-indazole-4,6'-hexahydropyrimidine]-2',4'-dione
(Example 1, step 6) was dissolved in DMF (200 ml) and cesium
carbonate (14.12 g, 43.34 mmol, 1.5 equiv.) and iodomethane (4.92
g, 2.16 ml, 34.67 mmol, 1.2 equiv.) were added at room temperature.
The mixture was stirred for 1 hour at room temperature. The
reaction mixture was poured into water and extracted three times
with ethyl acetate. The organic layers were washed with water and
brine, dried over sodium sulfate and evaporated to dryness. The
crude product was purified by flash chromatography on a silica gel
column eluting with an petroleum:ethyl acetate 10:1 to 1:1
gradient. The desired
(4S)-3'-(2,6-difluoro-4-iodo-phenyl)-1'-methyl-1-(2-trimethylsilylethoxym-
ethyl)spiro[6,7-dihydro-5H-indazole-4,6'-hexahydropyrimidine]-2',4'-dione
(15.7 g, 90% yield) was obtained as a yellow gum, MS: m/e=603.2
(M+H.sup.+).
Step 8:
(4S)-3'-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1'-methyl-1-(2-tr-
imethylsilylethoxymethyl)spiro[6,7-dihydro-5H-indazole-4,6'-hexahydropyrim-
idine]-2',4'-dione
[0069]
(4S)-3'-(2,6-Difluoro-4-iodo-phenyl)-1'-methyl-1-(2-trimethylsilyle-
thoxymethyl)spiro[6,7-dihydro-5H-indazole-4,6'-hexahydropyrimidine]-2',4'--
dione (Example 1, step 7) (12 g, 19.9 mmol) and phenylacetylene
(3.05 g, 3.32 ml, 29.9 mmol, 1.5 equiv.) were dissolved in 120 ml
of THF. Triethylamine (10.1 g, 13.9 ml, 99.6 mmol, 5 equiv.),
bis-(triphenylphosphine)-palladium(II)dichloride (420 mg, 0.6 mmol,
0.03 equiv.), triphenylphosphine (313 mg, 1.2 mmol, 0.06 equiv.)
and copper(I)iodide (114 mg, 0.6 mmol, 0.03 equiv.) were added and
the mixture was stirred for 3 hours at 60.degree. C. The reaction
mixture was evaporated with Isolute.RTM.. The crude product was
purified by flash chromatography on a silica gel column eluting
with an ethyl acetate:heptane 30:70 to 100:0 gradient. The desired
(4S)-3'-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1'-methyl-1-(2-trimethyl-
silylethoxymethyl)spiro[6,7-dihydro-5H-indazole-4,6'-hexahydropyrimidine]--
2',4'-dione (11.2 g, 98% yield) was obtained as a brown foam, MS:
m/e=577.3 (M+H.sup.+).
Step 9:
(4S)-3'-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1'-methyl-spiro[1-
,5,6,7-tetrahydroindazole-4,6'-hexahydropyrimidine]-2',4'-dione
[0070] The title compound was obtained as a white foam, MS:
m/e=447.2 (M+H.sup.+), using chemistry similar to that described in
Example 1, step 4 by stirring the reaction for 2 hours at
80.degree. C. starting from
(S)-1'-(2,6-difluoro-4-(phenylethynyl)phenyl)-3'-methyl-2-((2-(trimethyl
silyl)ethoxy)methyl)-2,5,6,7-tetrahydro-1'H-spiro[indazole-4,4'-pyrimidin-
e]-2',6'(3'H,5'H)-dione (Example 1, step 8).
Step 10:
(4S)-3'-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-2-ethyl-1'-methy-
l-spiro[6,7-dihydro-5H-indazole-4,6'-hexahydropyrimidine]-2',4'-dione
[0071] The title compound was obtained as a white solid, MS:
m/e=475.4 (M+H.sup.+), using chemistry similar to that described in
Example 1, step 7 starting from
(4S)-3'-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1'-methyl-spiro[1,5,6,7--
tetrahydroindazole-4,6'-hexahydropyrimidine]-2',4'-dione (Example
1, step 9) and iodoethane. The desired
(4S)-3'-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-ethyl-1'-methyl-spiro[-
6,7-dihydro-5H-indazole-4,6'-hexahydropyrimidine]-2',4'-dione was
obtained by separation of the two formed isomers using a Reprosil
Chiral NR.RTM. column with heptane:ethanol 60:40 mixture as eluent
collecting peak A.
Example 2
(4S)-3'-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1-ethyl-1'-methyl-spiro[6-
,7-dihydro-5H-indazole-4,6'-hexahydropyrimidine]-2',4'-dione
##STR00009##
[0073] The title compound was obtained as a white solid, MS:
m/e=475.4 (M+H.sup.+), using chemistry similar to that described in
Example 1, step 7 starting from
(4S)-3'-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1'-methyl-spiro[1,5,6,7--
tetrahydroindazole-4,6'-hexahydropyrimidine]-2',4'-dione (Example
1, step 9) and iodoethane. The desired
(4S)-3'-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1-ethyl-1'-methyl-spiro[-
6,7-dihydro-5H-indazole-4,6'-hexahydropyrimidine]-2',4'-dione was
obtained by separation of the two formed isomers using a Reprosil
Chiral NR.RTM. column with heptane:ethanol 60:40 mixture as eluent
collecting peak B.
* * * * *