Title of Invention

1- ARYLSULPHONYL - 2- ARYL - PYRROLIDINE AND PIPERIDINE COMPOUNDS

Abstract This invention relates to l-arylsulphonyl-2-aryl-pyrrolidine and piperidine compounds of the general formula wherein R' signifies hydrogen or (C1-C7)-alkylj R2 signifies furyl, thienyl, pyridyl or ph-enyl, which is optionally substituted by 1 to 3 substituents, selected from (C,-C7)-alkyl, (Ct-C7)-alkoxy, halogen, cyano, CF30r -N(R4)2; R3 signifies naphthyl or phenyl, which is optionally substituted by 1 to 3 substituents, selected from (C,-C7 )-alkyl, (C1-C7 )-alkoxy, halogen, acetyl, cyano, hydroxy-( C,-C7)-alkyl, ~CH2-morpholi.n-4-yl, (C1-C7)-alk-yl-oxy-(C,-C7 )-alkyl, (C1-C7)-alkyl~N(R4)2 or CF3; R4 signifies, independently from each other, hydrogen or(C1-C7)-a1kyl, with the exception of (RS)-2-phenyl-l-( toluene-4-sulfonyl)-pyrrolidine, (RS)-l- (toluene-4-sulfo nyl) -2 -p- tolyl-pyrrolidine, N -tosyl-cis-3-methyl- 2-phenyl pyrrolidine, 3-[1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]pyridine and N-tosyl-2-(3,4- dim ethoxy- phenyl) -pyrrolidin e, as well as their pharmaceutically acceptable salts.
Full Text

l-Arenesulfonvl-2-arvI-pvrrolidine and piperidine derivatives
The present invention is concerned with l-arenesulfonyl-2-aryl-pyrrolidine and piperidine derivatives of the general formula
wherein
R1 signifies hydrogen or lower alkyl;
R signifies furyl, thienyl, pyridyl or phenyl, which is optionally
substituted by 1 to 3 substituents, selected from lower alkyl, lower
alkoxy, halogen, cyano, CF3 or -N(R4)2;
R3 signifies naphthyl or phenyl, which is optionally substituted by 1 to 3
substituents, selected from lower alkyl, lower alkoxy, halogen, acetyl,
cyano, hydroxy-lower alkyl, -CH2-morpholin-4-yl, lower alkyl-oxy-
lower alkyl, lower alkyl-N(R4)2 or CF3;
' R4 . "'■■ signifies, independently from each other, hydrogen or lower alkyl,
as well as their pharmaceutical^ acceptable salts.
Compounds of formula I are novel with the exception of (RS)-2-phenyl-l~ (toluene-4-sulfonyl)-pyrrolidine, (RS)-l-(toluene-4-sulfonyl)-2-p-tolyl-pyrrolidine, N-tosyl-cis-3-methyl-2-phenyI pyrrolidine, 3-[ l-(toluene-4-sulfonyl)-pyrrolidin-2-yljpyridine and N-tosyl-2-(3,4-dimethoxy-phenyl)-pyrrolidine. The manufacture of these compounds is described in J. Org. Chem., 51, (1986) 4089-4090. Furthermore, the preparation of (RS)-2-phenyl-l-(toluene-4-sulfonyl)-pyrrolidine is described in Liebigs Ann. Chem., 762, (1972) 93-105,

It has surprisingly been found that the compounds of general formula I are metabotropic glutamate receptor antagonists and/or agonists. Compounds of formula I are distinguished by valuable therapeutic properties.
In the central nervous system (CNS) the transmission of stimuli takes place by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreceptor.
L-glutamic acid, the most commonly occurring neurotransmitter in the CNS, plays a critical role in a large number of physiological processes. The glutamate-dependent stimulus receptors are divided into two main groups. The first main group forms ligand-controlled ion channels. The metabotropic glutamate receptors (mGluR) belong to the second main group and, furthermore, belong to the family of G-protein-coupled receptors.
At present, eight different members of these mGluR are known and of these some even have sub-types. On the basis of structural parameters, the different influences on the synthesis of secondary metabolites and the different affinity to low-molecular weight chemical compounds, these eight receptors can be sub-divided into three sub-groups:
mGluRl and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and mGIuR4, mGluR6, mGluR7 and mGluR8 belong to group III.
Ligands of metabotropic glutamate receptors belonging to the first group can be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits, as well as chronic and acute pain.
Other treatable indications in this connection are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depressions.
Objects of the present invention are compounds of formula I and their pharmaceutical^ acceptable salts per se and as pharmaceutical^ active substances, their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of the compounds in accordance with the invention in

the control or prevention of illnesses of the aforementioned kind, and, respectively, for the production of corresponding medicaments.
Preferred compounds of formula I in the scope of the present invention are those, in which Rl signifies hydrogen or methyl; R2 signifies phenyl, optionally substituted by halogen, lower alkyl, CF3 or -N(CH3)2, with the exception of (RS)-2-phenyl-l-(toluene-4-sulfonyl)-pyrrolidine, (RS)-l-(toluene-4-sulfonyl)-2-p-tolyl-pyrrolidine, N-tosyl-cis-3-methyl-2-phenyl pyrrolidine, 3-[l-(toluene-4-sulfonyl)-pyrrolidin-2-yl] pyridine and N-tosyl-2-(3,4-dimethoxy-phenyl)-pyrrolidine and their salts. The following are examples of such compounds: (RS)-2-(3-fluoro-phenyl)-l-(toluene-4-sulfonyl)-pyrrolidine, (RS)-l-(4-chloro-benzenesulfonyl)-2-(3-fluoro-phenyl)-pyrrolidine, (RS)-l-(4-chloro-benzenesulfonyl)-2-phenyl-pyrrolidine, (RS)-2-(4-chloro-phenyl)-l-(toluene-4-sulfonyl)-pyrrolidine, (RS)-i-(4-chloro-benzenesulfonyl)-2-(4-fluoro-phenyl)-pyrrolidine, (RS)-2-(4-fluoro-phenyl)-l-(toluene-4-sulfonyl)-pyrrolidine, (RS)-l-benzenesulfonyl-2-(4-chloro-phenyl)-pyrrolidine, (RS)-l-(4-fluoro-benzenesulfonyl)-2-(4-fluor6-phenyl)-pyrrolidine, (RS)-2-(4-fluoro-phenyl)-l-(toluene-2-sulfonyl)-pyrrolidine, (RS)-l-(4-chloro-benzenesulfonyl)-2-p-tolyl-pyrrolidine, (RS)-l-(4-ethyl-benzenesulfonyl)-2-(4-fluoro-phenyl)-pyrrolidine, (RS)-l-(toluene-4-sulfonyl)-2-m-tolyl-pyrrolidine, (RS)-2-(3-chloro-phenyl)-l-(toluene-4-sulfonyl)-pyrrolidine, (RS)-2-(3,4-difluoro-phenyl)-l-(toluene-4-sulfonyl)-pyrrolidine, (RS)-2-(3-chloro-4-fluoro-phenyl)-l-(toluene-4-sulfonyl)-pyrrolidine, (RS)-l-(4-fluoro-benzenesulfonyl)-2-(4-dimethylamino-3-chloro-phenyl)-pyrrolidine,
(RS)-l-(toluene-4-sulfonyl)-2-(4-trifluoromethyl-phenyl)-pyrrolidine, (RS)-2-(4-chloro-3-methyl-phenyl)-l-(toluene-4-sulfonyl)-pyrrolidine, (RS)-2-(4-fluoro-phenyl)-l-(4-trifluoromethyl-benzenesulfonyl)-pyrrolidine, (RS)-2-(N,N-dimethylamino-phenyl)-l-(4-fluoro-benzenesulfonyl)-pyrrolidine, (R)-l-(4-chloro-benzenesulfonyl)-2-(4-fluoro-phenyl)-pyrrolidine, (S)-l-(4-chloro-benzenesulfonyl)-2-(4-fluoro-phenyl)-pyrrolidine, (RS)-2-(4-ethyl-phenyl)-l-(toluene-4-sulfonyl)-pyrrolidine, (RS)-2-(4-ethyl-phenyl)-l-(4-fluoro-benzenesulfonyl)-pyrrolidine, (S)-2-(4"fluoro-phenyl)-l-(toluene-4-sulfonyl)-pyrrolidine,

(R)-2-(4-fluoro-phenyl)-l-(toluene-4-sulfonyl)-pyrrolidine)
(RS)-2-(4-fluoro-phenyl)-l-(4-methoxymethyl-benzenesulfonyl)-pyrrolidineand
(2RS,3RS)-2-(4-fluoro-phenyl)-3-methyl-l-(toluene-4-sulfonyl)-pyrrolidine
Compounds of formula 1, in which R1 signifies hydrogen; and R2 signifies furyl, thienyl or pyridyl; are also preferred.
The following are examples of such compounds: (RS)-l-(4-chloro-benzenesulfonyl)-2-thien-2-yl-pyrrolidine, (RS)-2-thien-2-yl-l-(toluene-4-sulfonyl)-pyrrolidine and (RS)-2-thien-3-yl-l-(toluene-4-sulfonyI)-pyrrolidine.
The invention embraces all stereoisomeric forms in addition to the racemates.
The term "lower alkyl" used in the present description denotes straight-chain or branched saturated hydrocarbon residues with 1-7 carbon atoms, preferably with 1-4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl and the like.
The term "lower alkoxy" denotes a lower alkyl residue in the sense of the foregoing definition bonded via an oxygen atom.
The term "halogen" embraces fluorine, chlorine, bromine and iodine.
The compounds of general formula 1 and their pharmaceutically acceptable salts can be manufactured by
reacting a compound of the formula


II

with a compound of formula
hal

0=S—R3

III

O

and, it desired,
converting a functional group in a compound of formula I into another functional group
and, if desired,
converting a compound of formula I into a pharmaceutical^ acceptable salt.
In accordance with the invention, an appropriately substituted compound of formula II, for example (RS)-2-(3-fluoro-phenyl)-pyrrolidine, is reacted with a suitable compound of formula III, for example toluene-4-sulfonyl chloride. The reaction according to known methods takes place at room temperature within 16 hours in an inert solvent, for example in dichloromethane. After evaporating the solvent, the mixture is dissolved in water and extracted with a suitable solvent, for example ethyl acetate and purified using known methods.
In particular, cyano groups can be hydrogenated to amino groups or halogen atoms in halogenated lower alkyl groups can be substituted with amins or converted to ethers.
The hydrogenation is preferrably effected with Raney-nickel at room temperature under normal pressure and the amino group can be alkylated by known methods.
The ether formation of benzylchloride derivatives can be conveniently carried out as follows: A compound of general formula I which contains a halogenated lower alkyl group, for example (RS)-2-(4-fluoro-phenyl)-l-(4-chloromethyl-benzenesulfonyl)-
pyrrolidine is reacted with sodium methanolate in MeOH for 80 hours at 50°C and purified using known methods.
The substitution of a halogen atom in a halogenated lower alkyl group with an amine can be conveniently carried out as follows: A compound of general formula I which contains a halogenated lower alkyl group, for example (RS)-2-(4-fluoro-phenyl)-l-(4-chloromethyl-benzenesulfonyl)-pyrrolidine is reacted with morpholine in DMF for 17
hours at 80°C and purified using known methods.
The pharmaceutically acceptable salts can be manufactured readily according to methods known per se and taking into consideration the nature of the compound to be converted into a salt. Inorganic or organic acids such as, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like are suitable for the formation of pharmaceutically acceptable salts of basic compounds of formula I. Compounds which contain the alkali

metals or alkaline earth metals, for example sodium, potassium, calcium, magnesium or the like, basic amines or basic amino acids are suitable for the formation or pharmaceutically acceptable salts of acidic compounds.
Scheme 1 gives an overview of the manufacture of the compounds of formula I starting from known compounds. Substituents Rl present in the compounds of formula I are introduced according to methods known to the person skilled in the art. The manufacture of representative compounds of formula I is described in detail in examples 1-91.
Scheme 2 and scheme 3 give an overview of the conversions of functional groups in compounds of formula I described in detail in examples 85-87.






The compounds of formula I and their pharmaceutically acceptable salts are, as already mentioned above, metabotropic glutamate receptor agonists and/or antagonists and can be used for the treatment or prevention of acute and/or chronic neurological disorders, such as psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits, as well as acute and chronic pain. Other treatable indications are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are Alzheimer's disease, Huntington's chorea, ALS, dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficient functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, psychoses, opiate addiction, anxiety, vomiting, dyskinesia and depression. The compounds of the present invention are group I mGlu receptor agonists and/or antagonists. It has been shown that the compounds of examples 1 - 4, 6, 8,9,11 - 14, 16, 19, 21, 25, 26, 28, 29, 31, 38, 39, 40,42, 48, 55, 56, 58, 60, 69, 72, 76, 77, 78, 81, 82, 83, 84, 85, 88, 89 and 90 show agonistic activity, the other specific examples have an antagonistic activity to the mGlu receptor. The compounds show activities, as measured in

the assay described below, of 50 \xM or less, typically 3 J0.M or less, and ideally of 0.5 |oM or less.
In the table below are shown some specific activity-data:

cDNA encoding rat mGlu la receptor obtained from Prof. S. Nakanishi (Kyoto, Japan) was transiently transfected into EBNA cells using a procedure described by Schlaeger et. al, New Dev. New Appl. Anim. Cell Techn., Proc. ESACT Meet., 15th (1998),
105-112 and 117-120. [Ca2+]i measurements were performed on mGlu la transfected EBNA cells after incubation of the cells with Fluo-3 AM (0.5 |iM final concentration) for 1 hour at 37°C followed by 4 washes with assay buffer (DMEM supplemented with Hank's salt and 20 mM HEPES. [Ca2+]i measurements were done using a fluorometric imaging plate reader (FLIPR, Molecular Devices Corporation, La Jolla, CA, USA). When compounds were evaluated as antagonists they were tested against 10 pM glutamate as agonist.
The inhibition (antagonists) or activation (agonists) curves were fitted with a four parameter logistic equation giving EC50, IC301 and Hill coefficient using the iterative non linear curve fitting software Origin (Microcal Software Inc., Northampton, MA, USA).
The compounds of formula I and pharmaceutical^ 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 admini-

stration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
The compounds of formula I 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 gelatine capsules. Suitable carriers for soft gelatine 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 gelatine 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 I, 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.
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.
As mentioned earlier, medicaments containing a compound of formula I or a pharmaceutically acceptable salt 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 I 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.
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.

Finally, as mentioned earlier, the use of compounds of formula I and of pharmaceutical^ acceptable salts thereof for the production of medicaments, especially for the control or prevention of acute and/or chronic neurological disorders of the aforementioned kind, is also an object of the invention.
Example 1
(RS)-2-(3-Fluoro-phenvl)-l-ftoluene-4-sulfonvl)-pvrrolidine
a) 3-Dimethylamino-l-(3-fluoro-phenyl)-propan-l-one hydrochloride (1:1)
A stirred mixture of 3-fluoro-acetophenone (10.5 g, 75.7 mmol), paraformaldehyde (3.79 g, 126 mmol), dimethylamine hydrochloride (6.17 g, 75.7 mmol), cone. HC1 (0.2 ml) and ethanol (17 ml) was refluxed for 1.5 h. The clear solution was cooled to 0°C and diethyl ether (100 ml) was added. The formed white solid was collected, washed with diethyl ether and recrystallized from EtOH/diethyl ether to yield the product (10.2 g, 58 %) as a white solid, m.p. 152°C and MS: m/e = 195 (M+).
b) 4-(3-Fluoro-phenvl)-4-oxo-butvronitrile
A stirred mixture of 3-dimethylamino-l-(3-fluoro-phenyl)-propan-l-one hydrochloride (5.20 g, 22.4 mmol) and potassium cyanide (2.19 g, 33.6 mmol) was refluxed for 17 h, evaporated, dissolved in water (150 ml) and extracted with ethyl acetate (2 x 120 ml). The combined organic layers were washed with water (120 ml), brine (120 ml), 3N sulfuric acid (100 ml) and brine (100 ml), dried (MgSOa) and evaporated to give an orange oil (2.15 g) which was further purified by column chromatography on silica gel (ethyl acetate/hexane 1:3) to yield the product (1.68 g, 42%) as a pale yellow solid, m.p. 46°C and MS: m/e = 177 (M+).
c) 5-(3-Fluoro-phenvl)-3^4-dihvdro-2H-pvrrole
4-(3-Fluoro-phenyl)-4-oxo-butyronitrile (1.60 g, 9.03 mmol) dissolved in MeOH (45 ml) and 3.5 N MeOH-NH3 (45 ml) was hydrogenated on Ra-Ni at RT for 16 h. The catalyst was filtered off, the filtrate evaporated and the crude product purified by column chromatography on silica gel (ethyl acetate/toluene 1:2) to give the product (1.16 g, 79%) as a colorless oil, MS: m/e = 163 (M+).
d) (RSV2-(3-Fluoro-phenvlVpyrrolidine

To a stirred solution of 5-(3-fluoro-phenyl)-3,4-dihydro-2H-pyrrole (1.10 g, 6.74 mmol) n methanol (40 ml) was added at 0°C sodium borohydride (0.51 g, 13.4 mmol) and the •eaction mixture was stirred at RT for 1 h. Then additional sodium borohydride (0.25 g, 5.61 mmol) was added and stirring was continued for lh. The mixture was evaporated, dissolved in saturated NaHCCV solution (70 ml) and extracted with dichloromethane (2 x 70 ml). The combined organic layers were washed with brine (70 ml), dried (MgSO^) and evaporated. The crude product was purified by column chromatography on silica gel ;dichloromethane/MeOH/NH4OH 15:1:0.1) to give the product (0.77 g, 69%) as a colorless oil, MS: m/e = 165 (M+).
t) (RS)-2-f3-Fluoro-phenvn-l-(toluene-4-sulfonvl)-pvrroIidine
To a stirred solution of (RS)-2-(3-fluoro-phenyl)-pyrrolidine (0.24 g, 1.45 mmol) and triethylamine (0.40 ml, 2.87 mmol) in dichloromethane (40 ml) was added at0°C toluene-4-sulfonyl chloride (0.42 g, 2.20 mmol). The mixture was stirred at RT for 16 h, evaporated, dissolved in water (40 ml) and extracted with ethyl acetate (2 x 40 ml). The combined organic layers were washed with water (40 ml), brine (40 ml), dried (MgS04) and evaporated. The crude product was purified by crystallization from ethyl acetate/hexane to give the product (0.38 g, 83%) as a white solid, m.p. 116°C and MS: m/e = 319(M+).
Example 2
(RS)-l-(4-Chloro-benzenesulfonvl)-2-(3-fluoro-phenvl)-pyrrolidine
The title compound, white solid, m.p. 126°C and MS: m/e = 339 (M+) was prepared in accordance with the general method of example le from (RS)-2-(3-fluoro-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Example 3
(RS)-4-l;l-(Toluene-4-sulfonvl)-pvrrolidin-2-vn-pvridine
The title compound, pale brown solid, m.p. 158°C and MS: m/e = 302 (M+) was prepared in accordance with the general method of example le from (RS)-4-(2-pyrrolidinyl)-pyridine and toluene-4-sulfonyl chloride.

Example 4
(RS)-2"Phenvl"l-(toluene-4-sulfonvl)-pvrrolidine
The title compound, white solid, m.p. 109°C and MS: m/e = 301 (M+) was prepared in accordance with the general method of example le from (RS)-2-phenyl-pyrrolidine and toluene-4-sulfonyl chloride.
Example 5
(RS)-l-Benzenesulfonvl-2-phenvl-pvrrolidine
The title compound, light pink solid, m.p. 116°C and MS; m/e = 287 (M+) was prepared in accordance with the general method of example le from (RS)-2-phenyl-pyrrolidine and benzenesulfonyl chloride.
Example 6
(RS)-l-f4-Chloro-ben2enesulfonvl)-2-phenvl-pvrrolidine
The title compound, pale pink solid, m.p. 119°C and MS; m/e = 321 (M+) was prepared in accordance with the general method of example le from (RS)-2-phenyl-pyrrolidineand4-chloro-benzenesulfonyl chloride.
Example 7
(RS)-l-Ben2enesulfonvl-2-(4-fluoro-phenvl)-pvrrolidine
The title compound, white solid, m.p. 100°C and MS: m/e = 305 (M+) was prepared in accordance with the general method of example le from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and benzenesulfonyl chloride.
Example 8
(RS1)-2-(4-Chloro-phenvl)-l-(toluene-4-sulfonvl)-pvrrolidine
The title compound, white solid, m.p. 121°C and MS: m/e = 335 (M+) was prepared in accordance with the general method of example le from (RS)-2-(4-chloro-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.

Example 9
(RS)-l-(4-Chloro-benzenesulfonvl)-2-(4-chloro-phenvn-pvrrolidine
The title compound, white solid, m.p. 159°C and MS: m/e = 355 (M+) was prepared in accordance with the general method of example le from (RS)-2-(4-chloro-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Example 10
(RS)-2-f4-Fluoro-phenvl)-l-f4-methoxv-benzenesulfonvn-pvTrolidine
The title compound, white solid, m.p. 134°C and MS: m/e = 335 (M+) was prepared in accordance with the general method of example le from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-methoxy-benzenesulfonyl chloride.
Example 11
(RS)-l-(4-Chloro-benzenesulfonvl)-2-(4-fluorophenvI)-pvrrolidine
The title compound, white solid, m.p. 118°C and MS: m/e = 339 (M+) was prepared in accordance with the general method of example le from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Example 12
(RS)-2-(4-Fluoro-phenvl)-l-(toluene-4-sulfonyl)-pvrrolidine
The title compound, off-white solid, m.p. 128°C and MS: m/e = 319 (M+) was prepared in accordance with the general method of example le from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Example 13
(RS)-l-Benzenesulfonvl-2-(4-chloro-phenvl)-pvrrolidine
The title compound, white solid, m.p. 122°C and MS: m/e = 321 (M+) was prepared in accordance with the general method of example le from (RS)-2-(4-chloro-phenyl)-pyrrolidine and benzenesulfonyl chloride.

Example 14
(RS)"4-[l-(4-Chloro-benzenesulfonvl)-pvrrolidin-2-vll-pvridine
The title compound, white solid, m.p. 177°C and MS: m/e = 322 (M+) was prepared in accordance with the general method of example le from (RS)-4-(pyrrolidin-2-yl)-pyridine and 4-chloro-benzenesulfonyl chloride.
Example 15
(RS)-l-Ben2enesulfonvl-2-(3-fluoro-phenvl)-pvTrolidine
The title compound, white solid, m.p. 96°C and MS: m/e = 305 (M+) was prepared in accordance with the general method of example le from (RS)-2-(3-fluoro-phenyl)-pyrrolidine and benzenesulfonyl chloride.
Example 16
(RS)-l-(4-Fluoro-benzenesulfonvl)-2-(4-fluoro-phenvl)-pvTroIidine
The title compound, light brown solid, m.p. 121°CandMS: m/e = 324.2 (M+H+) was prepared in accordance with the general method of example le from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Example 17
fRS)-2-(4-Fluoro-phenvl)-l-(toluene-3-sulfonyI)-pvrrolidine
The title compound, light brown solid, m.p. 102°C and MS: m/e = 319 (M+) was prepared in accordance with the general method of example le from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and toluene-3-sulfonyl chloride.
Example 18
(RS)-2-f4-Fluoro-phenvl)-l-(toluene-2-sulfonvl)-pvrrolidine
The title compound, colorless oil, MS: m/e = 319 (M+) was prepared in accordance with the general method of example le from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and toluene-2-sulfonyl chloride.

Example 19
(RS)-l-fToluene-4-suIfonvn-2-p-tolvl-pvrroIidine
The title compound, white solid, m.p. 124°C and MS: m/e = 315 (M+) was prepared in accordance with the general method of example le from (RS)-2-p-tolyl-pyrrolidine and toluene-4-sulfonyl chloride.
Example 20
fRS)-l-(4-Chloro-benzenesulfonvl)-2-p-tolvl-pvrrolidine
The title compound, white solid, m.p. 129°C and MS: m/e = 335 (M+) was prepared in accordance with the general method of example le from (RS)-2-p-tolyl-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Example 21
(RS)-l-('4-Ethvl-benzenesulfonvl)-2-(4-fluoro-phenvI)-pvrrolidine
The title compound, white solid, m.p. 78°C and MS: m/e = 333 (M+) was prepared in accordance with the general method of example le from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-ethyl-benzenesulfonyl chloride.
Example 22
(RS)-2-(4-Fluoro-phenvn-l-(4'isopropvl-benzenesulfonvl)-pvrrolidine
The title compound, white solid, m.p. 77°C and MS: m/e = 347 (M+) was prepared in accordance with the general method of example le from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-isopropyl-benzenesulfonyl chloride.
Example 23
(R$)-l-(4-Fluoro-benzenesulfonvD-2-p-tolvl-pvrrolidine
The title compound, white solid, m.p.H2°C and MS: m/e = 319 (M+) was prepared in accordance with the general method of example le from (RS)-2-p-tolyl-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.

Example 24
fRS)-l-(4-Chloro-benzenesulfonvl)-2-(4-methoxv-phenvl)-pvrrolidine
The title compound, white solid, m.p. 133°C and MS: m/e = 352 (M+H*) was prepared in accordance with the general method of example le from (RS)-2-(4-methoxy-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Example 25
(RSV2-(4-Methoxy-phenvl)-l-(toluene-4-suIfonvl)-pvrroIidine
The title compound, white solid, m.p. 122°C and MS: m/e = 332 (M+H+) was prepared in accordance with the general method of example le from (RS)-2-(4-methoxy-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Example 26
(RS)-l-(4-Bromo-benzenesulfonvl)-2-(4-fluoro-phenvl)-pvrrolidine
The title compound, off-white solid, m.p. 131°C and MS: m/e = 383 (M+) was prepared in accordance with the general method of example le from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-bromo-benzenesulfonyl chloride.
Example 27
(RS)-l-{4-f2-(4-Fluoro-phenvl)-pvrrolidine-l-sulfonvll-phenvU-ethanone
The title compound, pale brown solid, m.p. 148°C and MS: m/e = 348 (M+H+) was prepared in accordance with the general method of example le from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-acetyl-benzenesulfonyl chloride.
Example 28
(RS)-l-(Toluene-4-sulfonyl)-2-m-tolvl-pvrrolidine
The title compound, off-white solid, m.p. 79°C and MS: m/e = 315 (M+) was prepared in accordance with the general method of example le from (RS)-2-m-tolyl-pyrrolidine and toluene-4-sulfonyl chloride.

Example 29
fRS)-l-f4-ChlorO"benzenesulfonvl)-2-m-tolvl-pvrrolidine
The title compound, off-white solid, m.p. 78°C and MS: m/e = 335 (M+) was prepared in accordance with the general method of example le from (RS)-2-m-tolyl-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Example 30
(RS)-l-(4-Fluoro-benzenesulfonyl)-2-m-tolyl-pyrrolidine
The title compound, off-white solid, m.p. 80°C and MS: m/e = 319 (M+) was prepared in accordance with the general method of example le from (RS)-2-m-tolyl-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Example 31
(RS)-2-f3-Chloro-phenvl)-l-(toluene-4-sulfonvl)-pvrrolidine
The title compound, off-white solid, m.p, 107°C and MS: m/e = 335 (M+) was prepared in accordance with the general method of example le from (RS)-2-(3-chloro-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Example 32
(RS)-l-(4-ChIoro-benzenesulfonvl)-2-(3-chloro-phenvn-pvTrolidine
The title compound, light brown solid, m.p. 99°C and MS: m/e = 355 (M+) was prepared in accordance with the general method of example le from (RS)-2-(3-chloro-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Example 33
(RS)-2-(4-Fluoro-phenvl)-l-(4-cvano-benzenesulfonvl)-pvrrolidine
The title compound, off-white solid, m.p. 147°C and MS: m/e = 330 (M+) was prepared in accordance with the general method of example le from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-cyano-benzenesulfonyl chloride.

Example 34
fRS)-l-f4-Chloro-ben2enesulfonvl)-2-(3-methoxv-phenvl)-pvrrolidine
The title compound, white solid, m.p. 95°C and MS: m/e = 351 (M+) was prepared in accordance with the general method of example le from (RS)-2-(3-methoxy-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Example 35
(RS)-l-f4-Fluoro-ben2enesulfonvl)-2-thien-2-yl-pvrrolidine
The title compound, white solid, m.p. 97°C and MS: m/e = 312.1 (M+H+) was prepared in accordance with the general method of example le from (RS)-2-thien-2-yl-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Example 36
(RS)-l-(4-Chloro-benzenesulfonvI)-2-thien-2-vI-pvrrolidine
The title compound, white solid, m.p. 84°C and MS: m/e = 328.1 (M+H+) was prepared in accordance with the general method of example le from (RS)-2-thien-2-yl-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Example 37
(RS)-2-Thien-2-yl-l-(toluene-4-sulfonyl)-pyrrolidine
The title compound, white solid, m.p. 108°C and MS: m/e = 308.2 (M+H+) was prepared in accordance with the general method of example le from (RS)-2-thien-2-yl-pyrrolidine and toluene-4-sulfonyl chloride.
Example 38
(RS)-2-(3>4'Difluoro-phenvl)-l-(toluene-4-sulfonvl)-pvrrolidine
The title compound, white solid, m.p. 127°C and MS: m/e = 338.2 (M+H+) was prepared in accordance with the general method of example le from (RS)-2-(3,4-difluoro-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.

Example 39
fRS)-l-f4-Chloro-benzenesulfonvl)-2-(3,4-difluoro-phenvl)"pvrrolidine
The title compound, white solid, m.p. 121°C and MS: m/e = 358.1 (M+H+) was prepared in accordance with the general method of example le from (RS)-2-(3,4-difluoro-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyI chloride.
Example 40
(RS)-l-(4-Chloro-benzenesulfonvl)-2-(4-dimethvlamino-3-fluoro-phenvl)-pvrrolidine
The title compound, white solid, m.p. 99°C and MS: m/e = 383.2 (M+H+) was prepared in accordance with the general method of example le from (RS)-2-(4-dimethylamino-3-fluoro-phenyl)-pyrrolidine and 4-chloro -benzenesulfonyl chloride.
Example 41
(RS)"l-(p-Toluenesulfonvl)-2-(4-dimethvlamino-3-fluoro-phenvl)-pvrroIidine
The title compound, white solid, m.p. 66°C and MS: m/e = 363.1 (M+H+) was prepared in accordance with the general method of example le from (RS)-2-(4-dimethylamino-3-fluoro-phenyl)-pyrrolidine toluene-4-sulfonyl chloride.
Example 42
(RS)-2-(3-Chloro-4-fluoro-phenvl)-l-(toluene-4-sulfonvl)-pvrrolidine
The title compound, off-white solid, m.p. 96°C and MS: m/e = 354.2 (M+H+) was prepared in accordance with the general method of example le from (RS)-2-(3-chloro-4-fluoro-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Example 43
(RS)-l-(4-Chloro-benzenesulfonvl)-2-f3-chloro-4-fluoro-phenvl)-pvrroIidine
The title compound, off-white solid, m.p. 119°C and MS: m/e = 374.2 (M+H+) was prepared in accordance with the general method of example le from (RS)-2-(3-chloro-4-fluoro-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.

Example 44
(RS)-2-(3-ChlorO"4-fluoro-phenvl)-l-(4-fluoro-benzenesulfonvl)-pyrrolidine
The title compound, white solid, m.p. 116°C and MS: m/e = 358.1 (M+) was prepared in accordance with the general method of example le from (RS)-2-(3-chloro-4-fluoro-phenyl)-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Example 45
(RS)-l-(4-Chloro-benzenesulfonvl)-2-(4-dimethvlamino-3-chloro-phenvl)-pvrrolidine
The title compound, white solid, m.p. 103°C and MS: m/e = 398 (M*) was prepared in accordance with the general method of example le from (RS)-2-(4-dimethylamino-3-chloro-phenyl)-pyrrolidine and4-chloro-benzenesulfonyl chloride.
Example 46
(RS)-l-(4-fluoro-benzenesulfonvl')-2-(4-dimethvlamino-3-chloro-phenvl')-pvTrolidine
The title compound, off-white solid, m.p. 119°C and MS: m/e = 382 (M+) was prepared in accordance with the general method of example le from (RS)-2-(4-dimethylamino-3-chloro-phenyl)-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Example 47
(RS)-2-(3,4-Dichloro-phenvl)-l-(toluene-4-sulfonvl)-pvTrolidine
The title compound, off-white solid, m.p. 136°C and MS: m/e = 369 (M+) was prepared in accordance with the general method of example le from (RS)-2-(3,4-dichloro-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Example 48
(RS)-l-(Toluene-4-sulfonvl)-2-(4-trifluoromethvl-phenvl)-pvrrolidine
The title compound, white solid, m.p. 99°C and MS: m/e = 369 (M+) was prepared in accordance with the general method of example le from (RS)-2-(4-trifluoromethyl-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.

Example 49
(RS)-l-(4-Chloro-benzenesulfonvl)-2-(4-trifluoromethvl-phenvl)-pvTrolidine
The title compound, white solid, m.p. 107°C and MS: m/e = 3 (M+) was prepared in accordance with the general method of example le from (RS)-2-(4-trifluoromethyl-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Example 50
(RS)-l-(4-Fluoro-benzenesulfonvl)-2-(4-trifluoromethvl-phenvl)-pvrrolidine
The title compound, white solid, m.p. 114°C and MS: m/e = 373 (M+) was prepared in accordance with the general method of example le from (RS)-2-(4-trifluoromethyl-phenyl)-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Example 51
(RS)-2-(2"Chloro-phenvl)-l-(toluene-4-sulfonvlVpvrrolidine
The title compound, white solid, m.p. 149°C and MS: m/e = 336.2 (M+H+) was prepared in accordance with the general method of example le from (RS)-2-(2-chloro-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Example 52
(RS)-2-(2-Fluoro-phenvl)-l-(toluene"4-sulfonvl)-pvrrolidine
The title compound, white solid, m.p. 143°C and MS: m/e = 320.3 (M+H+) was prepared in accordance with the general method of example le from (RS)-2-(2-fluoro-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Example 53
(RS)-l-(4-Chloro-benzenesulfonvn-2"(2-fluoro-phenvl>)-pvrroHdine
The title compound, white solid, m.p. 134°C and MS: m/e = 340.2 (M-hH+) was prepared in accordance with the general method of example le from (RS)-2-(2-fluoro-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.

Example 54
(RS)-l-(4-Fluoro-benzenesulfonyl)-2-(2-fluoro-phenvl)-pvrrolidine
The title compound, white solid, m.p. 108°C and MS: m/e = 324.2 (M+H+) was prepared in accordance with the general method of example le from (RS)-2-(2-fluoro-phenyl)-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Example 55
(RS)-2-Thien-3-vl-l-(toluene-4-sulfonvl)-pvTrolidine
The title compound, white solid, m.p. 114°C and MS: m/e = 308.2 (M+H+) was prepared in accordance with the general method of example le from (RS)-2-thien-3-yl-pyrrolidine and toluene-4-sulfonyl chloride.
Example 56
(RS)-l-f4-Chloro-benzenesuIfonvl)-2-thien-3-vl-pvrroIidine
The title compound, white solid, m.p. 120°C and MS: m/e = 328.1 (M+H+) was prepared in accordance with the general method of example le from (RS)-2-thien-3-yl-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Example 57
(RS)"l-(4-Fluoro-benzenesulfonyl)-2-thien-3-yl-pvrrolidine
The title compound, white solid, m.p. 135°C and MS: m/e = 312.1 (M+H+) was prepared in accordance with the general method of example le from (RS)-2-thien-3-yl-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Example 58
(RS)-2-(4-Chloro-3-methvl-phenvl)-l-ftoluene-4-sulfonvl)-pvrrolidine
The title compound, white solid, m.p. 103°C and MS: m/e = 349 (M+) was prepared in accordance with the general method of example le from (RS)-2-(4-chloro-3-methyl-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.

Example 59
(RS)-2-f4-Fluoro-phenvI)-l-f4-propvl-benzenesulfonvl)-pvrrolidine
The title compound, colorless oil, MS: m/e = 347 (M+) was prepared in accordance with the general method of example le from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-propyl-benzenesulfonyl chloride.
Example 60
(RS)-2-(4-Fluoro-phenvl)-l-(4-trifluoromethvl-benzenesulfonvl)-pvTrolidine
The title compound, white solid, m.p. 85°C and MS: m/e = 373 (M+) "was prepared in accordance with the general method of example le from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-trifluoromethyl-benzenesulfonyl chloride.
Example 61
(RS)-2-(4-Fluoro-phenvl)-l-(2,4,6-trimethvl-benzenesulfonvl)-pvrrolidine
The title compound, white solid, m.p. 111°C and MS: m/e = 347 (M+) was prepared in accordance with the general method of example le from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 2,4,6-trimethyl-benzenesulfonyl chloride.
Example 62
(RS)-l-(3-Chloro-4-methvl-benzenesulfonvl)-2-(4-fluoro-phenvl)-pvrrolidine
The title compound, off-white solid, m.p. 134°C and MS: m/e = 353 (M+) was prepared in accordance with the general method of example le from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 3-chloro-4-methyl-benzenesulfonyl chloride.
Example 63
(RS)-l-(2-Fluoro-benzenesulfonvl)-2-(4-fluoro-phenvl)-pvrrolidine
The title compound, off-white solid, m.p.91°C and MS: m/e = 323 (M+) was prepared in accordance with the general method of example le from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 2-fluoro-benzenesulfonyl chloride.

Example 64
(RS)-l-(3-Fluoro-benzenesulfonvlV2-(4-fluoro-phenvlVpvrrolidine
The title compound, off-white solid, m.p. 101°C and MS: m/e = 323 (M+) was prepared in accordance with the general method of example le from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 3-fluoro-benzenesulfonyl chloride.
Example 65
(RS)-l-(2-Cyano-benzenesulfonvl)-2-(4-fluoro-phenvl)-pvrrolidine
The title compound, light green solid, m.p. 101°C and MS: m/e = 330 (M+) was prepared in accordance with the general method of example le from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 2-cyano-benzenesulfonyl chloride.
Example 66
(RS)-2-(4-Fluoro-phenvI)-l-(naphthalene-2-sulfonvl)-pvTrolidine
The title compound, off-white solid, m.p. 166°C and MS: m/e = 355 (M+) was prepared in accordance with the general method of example le from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and naphthalene-2-sulfonyl chloride.
Example 67
(RS)-2-(214-Dimethvl-phenvl)-l-(toluene-4-sulfonvl)-pvrrolidine
The title compound, white solid, m.p. 130°C and MS: m/e = 329 (M+) was prepared in accordance with the general method of example le from (RS)-2-(2,4-dimethyl-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Example 68
(RS)-2-(2,4-Dimethvl-phenvl)-l-(4-fluoro-benzenesulfonvl)-pvrrolidine
The title compound, white solid, m.p. 134°C and MS: m/e = 333 (M+) was prepared in accordance with the general method of example le from (RS)-2-(2,4-dimethyl-phenyl)-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.

Example 69
(RS)-2-Furan-2-vl-l-(toluene-4-sulfonvl)"pvrrolidine
The title compound, white solid, m.p. 58°C and MS: m/e = 291 (M+) was prepared in accordance with the general method of example le from (RS)-2-furan-2-yl-pyrrolidine and toluene-4-sulfonyl chloride.
Example 70
(RS)-l-(4-Fluoro-benzenesulfonvl)"2-furan-2-vl-pvrrolidine
The title compound, white solid, m.p. 69°C and MS: m/e = 295 (M+) was prepared in accordance with the general method of example le from (RS)-2-furan-2-yl-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Example 71
fRS)-l-(4-Chloro-benzenesulfonvI)-2-{liran-2-vl-pvrrolidine
The title compound, yellow oil, MS: m/e = 311 (M+) was prepared in accordance with the general method of example le from (RS)-2-furan-2-yl-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Example 72
('RS)-2-(4-N,N-Dimethvlamino-phenvl)-l-(toluene-4-sulfonvI)-pvrrolidine
The title compound, white solid, m.p. 132°C and MS: m/e = 345.3 (M+H+) was prepared in accordance with the general method of example le from (RS)-2-(4-N,N-dimethylamino-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Example 73
(RS)-2-(4-N,N-Dimethvlamino-phenvl)-l-(4-fluoro-benzenesulfonvl)-pvrrolidine
The title compound, white solid, m.p. 109°C and MS: m/e = 349.4 (M+H+) was prepared in accordance with the general method of example le from (RS)-2-(4-N,N-dimethylamino-phenyl)-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.

Example 74
(RS)-2-(4-N,N-Dimethvlamino-phenvI)-l-f 4-chloro-benzenesulfonyI)-pvrrolidine
The title compound, white solid, m.p. 117°C and MS: m/e = 365.2 (M+H+) was prepared in accordance with the general method of example le from (RS)-2-(4-N,N-dimethylamino-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Example 75
(RS)-l-Benzenesulfonvl-2-f4-trifluoromethyl'phenvI)-pvrrolidine
The title compound, white solid, m.p. 95°C and MS: m/e = 355 (M+) was prepared in accordance with the general method of example le from (RS)-2-(4-trifluoromethyl-phenyl)-pyrrolidine and benzenesulfonyl chloride.
Example 76
fR)-l-(4-Chloro-benzenesulfonvl)-2-(4-fIuoro-phenvl)"pvTroIidine
The title compound, white solid, m.p. 119°CandMS: m/e = 339 (M+) was prepared in accordance with the general method of example le from (R)-2-(4-fluoro-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Example 77
(S)-l-(4-Chloro-benzenesulfonyI)-2-(4-fluoro-phenvI)-pyrrolidine
The title compound, white solid, m.p. 120°C and MS: m/e = 339 (M+) was prepared in accordance with the general method of example le from (S)-2-(4-fluoro-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Example 78
(RS)-2-(4-Ethvl-phenvl)-l-ftoluene-4-sulfonvI)-pvrrolidine
The title compound, white solid, m.p. 92°C and MS: m/e = 330.3 (M+H+) was prepared in accordance with the general method of example le from (RS)-2-(4-ethyl-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.

Example 79
(RS)-2-(4-Ethvl-phenvl)-l-(4-chloro-benzenesulfonvl)*pvrrolidine
The title compound, white solid, m.p. 94°C and MS: m/e = 350.3 (M+) was prepared in accordance with the general method of example le from (S)-2-(4-ethyl-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Example 80
(RS)-2-(4-Ethvl-phenvl)-l-(4-fluoro-ben2enesulfonvl)-pvrrolidine
The title compound, white solid, m.p. 93°C and MS: m/e = 334.2 (M+H+) was prepared in accordance with the general method of example le from (S)-2-(4-ethyl-phenyl)-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Example 81
(R)-2-(4-Fluoro-phenvl)-l-(toIuene-4-sulfonvl)-pvrrolidine
* The title compound, white solid, m.p. 136°C, [a]D20 = +174° (c = 0.1 in CHC13) and MS:
m/e = 319 (M+) was prepared in accordance with the general method of example le from
(R)-2-(4-fluoro-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Example 82
(S)-2-(4-Fluoro-phenvl)-l-ftoluene-4-sulfonvI)-pvrrolidine
The-title compound, white solid, m.p. 136°C, [a]D20 = -172° (c = 0.1 in CHC13) and MS: m/e = 319 (M+) was prepared in accordance with the general method of example le from (S)-2-(4-fluoro-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Example 83
(RS)-3-fl-(Toluene-4-sulfonvl)-pvrrolidin-2'Vl1-pvridine
The title compound, white solid, m.p. 112°C, and MS: m/e = 302 (M+) was prepared in accordance with the general method of example le from 3-(pyrolidin-2-yl)-pyridine and toluene-4-sulfonyl chloride.

Example 84
(RS)-2-f4-Fluoro-phenvl)-l-f4-hvdroxvmethvl-benzenesulfonvl)-pvrrolidine
The title compound, white solid, m.p. 107°C, and MS: m/e = 336.2 (M+H+) was prepared in accordance with the general method of example le from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-hydroxymethyl-benzenesulfonyl chloride.
Example 85
(RS)-2-(4-Fluoro-phenvl)-l-(4-methoxvmethvl-benzenesulfonvl)-pvrrolidine
Reaction of (RS)-2-(4-fluoro-phenyl)-l-(4-chloromethyl-benzenes"ulfonyl)-pyrrolidine (0.50 g, 1.41 mmol), which was prepared in accordance with the general method of example le from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-bromomethyl-benzenesulfonyl chloride, with sodium methanolate in MeOH for 80 h at 50°C yielded after crystallization from EE/hexane 0.28 g (52%) of the title compound as a white solid, m.p. 115°C, and MS: m/e = 349 (M+).
Example 86
(RS)-4-(4-[2-(4-Fluoro-phenyl)-pvrrolidine-l-sulfonvn-benzvll-morpholine fumarate
(1:1)
Reaction of (RS)-2-(4-fluoro-phenyl)-l-(4-chloromethyl-benzenesulfonyl)-pyrrolidine
(0.50 g, 1.41 mmol), which was prepared in accordance with the general method of example le from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-bromomethyl-benzenesulfonyl chloride, with morpholine (K2CO3, DMF, 80°C, 17 h) and subsequent formation of the fumarate (MeOH, diethyl ether) yielded the title compound as an off-white solid, m.p. 136°C, and MS: m/e = 405.4 (M+H+).
Example 87
(RS)-4-[2-(4-Fluoro-phenvl)-pvrrolidine-l-sulfonvn-benzvlamine fumarate (1:0.5) Hydrogenationof (RS)-2-(4-fluoro-phenyl)-l-(4-cyano-benzenesulfonyl)-pyrrolidine(Ra-
Ni, MeOH-NH3) and subsequent formation of the fumarate (MeOH, diethyl ether) yielded the title compound as a white solid, m.p. 207°C, and MS: m/e = 335.2 (M+Ht).

Example 88 Mixture of (2RS>3RSV and (2RS,3SRV2-(4-fluoro-phenvn-3-methvl-l^toluene-4-sulfonyP-pvrrolidine
The title compound, off-white solid, m.p. 94°C and MS: m/e = 333 (M+) was prepared in accordance with the general method of example le from a mixture of (2RS,3RS)-and (2RS,3SR)-2-(4-fluoro-phenyl)-3-methyl-pyrrolidine and toluene-4-sulfonyl chloride.
Example 89 Mixture of (2RS,3RS)- and (2RS,3SR)-l-(4-chloro-benzenesulfonvn-2-f4-fluoro-phenyP-3-methvl-pyrrolidine
The title compound, off-white solid, m.p. 87°C and MS: m/e = 354.2 (M+H+) was prepared in accordance with the general method of example le from a mixture of (2RS,3RS)- and (2RS,3SR)-2-(4-fluoro-phenyl)-3-methyl-pyrrolidine and 4-chlorobenzene-sulfonyl chloride.
Example 90 (2RS
Example A Tablets of the following composition are produced in a conventional manner:
mg/Tablet
Active ingredient 100
Powdered, lactose 95
White corn starch 35
Polyvinylpyrrolidone 8
Na carboxymethylstarch 10
Magnesium stearate 2
Tablet weight 250
Example B Tablets of the following composition are produced in a conventional manner:
mg/Tablet
Active ingredient 200
Powdered, lactose 100
White corn starch 64
Polyvinylpyrrolidone 12
Na carboxymethylstarch 20
Magnesium stearate 4
Tablet weight 400

Example C
Capsules of the following composition are produced:
mg/Capsule
Active ingredient 50
Crystalline, lactose 60
Microcrystalline cellulose 34
Talc 5
Magnesium stearate 1
Capsule fill weight j[50
The active ingredient having a suitable particle size, the crystalline lactose and the microcrystalline cellulose are homogeneously mixed with one another, sieved and thereafter talc and magnesium stearate are admixed. The final mixture is filled into hard gelatine capsules of suitable size.


WE CLAIM:
1. l-arylsulphonyl-2-aryl pyrrolidine and piperidine compounds of
the general formula
wherein
R1 signifies hydrogen or (C1-C7)-alkyl;
R~ signifies furyl, thienyl, pyridyl or phenyl, which is optionally
substituted by 1 to 3 substituents, selected from (CrC7)-alkyl,
(Cj-C7)-alkoxyJ halogen, cyano, CF3or -N(R4);>;
R' signifies naphthyl or phenyl, which is optionally substituted by 1 to 3
substituents, selected from (C1-C7)-alkyl> (C1-C7)-alkoxy> halogen,
acetyl, cyano, hydroxy-(C1-C7)-alkyl, -CH:>-morpholin-4-yl,
(CrC7)-alkyl-oxy-(CrC7)-alkyl) (CrC7)-alkyl-N(R4)2 or CF3;
R4 signifies, independently from each other, hydrogen or(C1-C7)-alkyi>
with the exception of (RS)-2-phenyl-l-(toluene-4-sulfonyl)-pyrrolidine, (RS)-l-
(toluene^-sulfonyl^-p-tolyl-pyrrolidine, N-tosyI-cis-3-methyl-2~phenyl
pyrrolidine, 3-[l-(toluene-4-sulfonyl)-pyrrolidin-2-yl]pyridine and N-tosyl-2-(3,4~
dimethoxy-pheriyl)-pyrrolidine,
as well as their pharmaceutical^ acceptable salts.
2. The compounds as claimed in claim 1, wherein
R signifies hydrogen or methyl;
R signifies phenyl, optionally substituted by halogen, (Q-C7)-alkyl, CF3 or
-N(CH>)2; and pharmaceutically acceptable salts thereof.
3. The compounds as claimed in claims 1 and 2, which are (RS)-2-(3-fluoro-phenyl)-l-(toluene-4-sulfonyl) -pyrrolidine,

(RS)-l-(4-chloro-benzenesulfonyl)-2-(3-fluoro-phenyl)-pyrrolidtne,
(RS)-l-(4-chloro-benzenesulfonyl)-2-phenyl-pyrrolidine,
(RS)-2-(4-chloro-phenyl)-l-(toluene-4-suIfonyl)-pyrrolidine,
(RS)-l-(4-chloro-benzenesulfonyl)-2-(4-fluoro-phenyI)-.pyrrolidine,
(RS)-2-(4-fluoro-phenyl}-l-(toluene-4-sulfonyl)-pyrrolidine,
(RS)-l-benzenesulfonyl-2-(4-chloro-phenyl)-pyrrolidine,
(RS-)-l-(4-fluoro-benzenesuIfonyI)-2-(4-fluoro-phenyl)-pyrrolidine,
(RS)-2-(4-fluoro-phenyl)-l-(toluene-2-su]fonyl)-pyrro!idinel
(RS)"l-(4-chloro-benzenesuIfonyl)-2-p'toIyl-pyrrolidine,
(RS)-l-(4-ethyl-benzenesulfonyl)-2-(4-fluoro-phenyl)-pyTrolidine,
(RS)"l-(toluerie-4-sulfonyl)-2-rn-tolyl-pyrrolidine,
(RS)-2-(3-chIoro-phenyI)-l-(toluene-4-su]fonyl)-pyrrolidine,
(RS)-2-(3)4-difluoro-phenyi)-l-(toluene-4-suIfonyl)-pyrrolidine,
(RS)-2-(3-chloro-4-fluoro-ph'enyl)-l-(toluene-4-sulfonyI)~pyrrolidine>
(RS)-l-(4-fluorobenzenesulfonyl)-2-(4-dimethylamino-3-chIoro-phenyl)-pyrrolidine1
(RS)-l-(toluene-4-sulfonyl)-2-(4-trifluoromet:hyl-phenyl)-pyrroIidine,
(RS)-2-(4-chloro-3-methyl-phenyl)-l-(toluene-4-sulfonyl)-pyrrolidine,
(RS)-2-(4-fluoro-phenyl)-l-(4-trifluoromethyl-benzenesulfonyl)-jpyrrolidine,
(RS)-2-(N>N-dimethylamino-phenyl)-l-(4-fluoro-benzenesulfonyI)-pyrrolidine)
(R)-l-(4-chloro-benzenesulfonyl)-2-(4-fluoro-phenyl)-pyrrolidine,
(S)-l-(4-chloro-benzenesulfonyl)~2-(4-fluoro-phenyl) -pyrrolidine,
(RS)-2-(4-ethyl-phenyl)-l-(toluene-4-sulfonyl)-pyrrolidine,
(RS)-2-(4-ethyl-phenyl)-l-(4-fl'uoro-benzenes'ulfonyl)-pyrrolidine?
(S)-2-(4-fluoro-phenyl)-l-(toluene-4-sulfonyl)-pyrrolidineJ
(R)-2-(4-fluoro-p'henyl)-l-(toluene-4-sulfonyl)-pyrrolidine,
(RS)-2-(4-fluoro-phenyl)-l-(4-methoxymethyl-benzenesulfonyl)-pyTrolidine and
(2RS,3RS)-2-(4-fluoro-phenyl)-3-methyl-]-(toluene-4-sulfonyl)-pyrrolidine.
4. The compounds as claimed in claim 1, wherein
Rl signifies hydrogen; and
R" signifies fur/1, thienyl or pyridyi.
5. The compounds as claimed in claims 1 and 4, which are (RS)-l-(4-chloro-benzenesulfonyl)-2-thien'2~yl-pyrrolidine, (RS)-2-thien-2-yl-l-(toluene-4-sulfonyl)-pyrrolidine and (RS)-2-thien-3-yl-l-(toluene-4-suIfonyl)-pyrrolidine.

6. A process for the manufacture of compounds as claimed in any one
of claims 1 to 5 as well as of pharmaceutically acceptable salts
thereof, which process reacting a compound of the formula

and, if desired,
converting a functional group in a compound of formula I into another functional
group and, if desired,
converting a compound of formula I into a pharmaceutically acceptable salt.
7. The compounds as claimed in claims 1 to 5, when manufactured
according to a process as claimed in claim 6.


Documents:

abs-in-pct-2001-1291-che.jpg

in-pct-2001-che-1291-abstract.pdf

in-pct-2001-che-1291-claims duplicate.pdf

in-pct-2001-che-1291-claims original.pdf

in-pct-2001-che-1291-correspondance others.pdf

in-pct-2001-che-1291-correspondance po.pdf

in-pct-2001-che-1291-description complete duplicate.pdf

in-pct-2001-che-1291-description complete original.pdf

in-pct-2001-che-1291-form 1.pdf

in-pct-2001-che-1291-form 26.pdf

in-pct-2001-che-1291-form 3.pdf

in-pct-2001-che-1291-form 5.pdf

in-pct-2001-che-1291-other documents.pdf

in-pct-2001-che-1291-pct.pdf

v.n.jpg


Patent Number 205040
Indian Patent Application Number IN/PCT/2001/1291/CHE
PG Journal Number 40/2007
Publication Date 05-Oct-2007
Grant Date 13-Mar-2007
Date of Filing 18-Sep-2001
Name of Patentee F. HOFFMANN-LA ROCHE AG
Applicant Address 124 GRENZACHERSTRASSE,CH-4070 BASLE,
Inventors:
# Inventor's Name Inventor's Address
1 MUTEL VINCENT 15 MARECHAUX, F-68100 MULHOUSE
2 VIEIRA BURGFELDERMATTWEG, CH-4123 ALLSCHWIL
3 WICHMANN ,JURGEN WOLFISCHBUHL 32, D-79585 STEINEN
PCT International Classification Number CO7D207/48
PCT International Application Number PCT/EP00/02431
PCT International Filing date 2000-03-18
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 99106004.7 1999-03-25 EUROPEAN UNION