Title of Invention

N-SUBSTITUTED 2-CYANOPYRROLIDINES

Abstract

This invention relates to compound of formula (IA) or (IB) wherein R' represents hydroxy, C1-C7alkoxy, C1-Cg-alkanoyloxy, or Rs~N-CO-O-, where ~ and Rs independently are C1-C7alkyl or phenyl which is unsubstituted or substituted by a substituent selected from C1-C7 alkyl, C1-C7alkoxy, halogen and trifluoromethyl and where ~ additionally is hydrogen; or ~ and Rs together represent C3-Csalkylene; and R" represents hydrogen; or R' and R" independently represent C1-C7alkyl; in free form or in form of a pharmaceutically acceptable acid addition salt.

Full Text

The present invention provides new dipeptidyl peptidasc-IV (DPP-IV) inhibitors which are effective in treating conditions mediated by DPP-IV. More recently, it was discovered that DPP-IV is responsible for inactivating glucagons-like peptide-1 (GLP-1). Since GLP-1 is a major stimulator of pancreatic insulin secretion and has direct beneficial effects on glucose disposal, DPP-IV inhibition appears to represent an attractive approach for treating conditions such as non-insulin-dependenl diabetes mellitus (NIDDM). R4 and Rj independently are Ci-Cyalkyl or phenyl which is unsubstituted or substituted by a substituenl selected from C1-C7 alkyl, C|-C7alkoxy, halogen and trifluoromethyl and where R4 additionally is hydrogen; or R4 and Rj together represent C^-Csalkylene; and R" represents hydrogen; or R" and R" independently represent Ci-Cyalkyl; in free fonn or in form of a phannacctitically acceptable acid addition salt. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolating or purifying the compounds of this invention. Although the preferred acid addition salts are the hydrochlorides, salts of methanesulfonic, sulfuric, phosphoric, citric, lactic and acetic acid may also be utilized. The compounds of the invention may exisl in the form of optically active isomers or diastereoisomers and can be separated and recovered by conventional techniques, such as chromatography. Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise The term "alkyl" refers to straight or branched chain hydrocarbon groups having 1 10 carton atoms, preferably 1 to 7 carbon atoms, most preferabiy 1 to 5 carbon atoms. Exemplary aJky) groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyi, hexyl and the like. The term "alkanoyl" refers to alkyl-C(O)-. The term "substituted adamantyl" refers to adamantyl, i.e. 1 - or 2-adamantyl, substituted by one or more, for example two, substitutents selected from alkyl, -ORi or -NR2R3; where Ri, R2 and R3 are independently hydrogen, alkyl, (Ci-Ce-alkanoyl), carbamv or -CO-NR4R5; where R4 and R5 are independently alkyl, unsubstituted or substituted aryl and where one of R^ and R5 additionally is hydrogen or R4 and R5 together represent Cr CTalkylene;. The term "aryl" preferably represents phenyl. Substituted phenyl preferabiy is phenyl substituted by one or more, e.g. two, substitutents selected from e.g. alkyl, alkoxy, halogen and trifluoromethyl. The temi "alkoxy" refers to alkyl-0-. The tenn "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine. The temri "alkylene" refers to a straight chain bridge of 2 to 7 carbon atoms, preferal of 3 to 6 carbon atoms, most preferably 5 carbon atoms. A prefen-ed group of compounds of the invention is the compounds of formula I wherein the substituent on the adamantyl is bonded on a bridgehead or a methylene adjacent to a bridgehead. Compounds of fonnula I wherein the giycyi-a-cyanopyn-olidine moiety is bonded to a bridgehead, the R" substituent on the adamantyl is preferably 3-hydroxy. Compounds of formula I wherein the glycyl-2-cyanopyrrolidine moiety is bonded a methylene adjacent to a bridgehead, the R" substituent on the adamantyl is preferably E hydroxy. wherein R" represents hydroxy, Ci-Cralkoxy, Ci-Ca-alkanoyloxy, or RsRtN-CO-O-, where R4 and R5 independently are CrC/alkyl or phenyl which is unsubstituted or substituted by a substituted seiected from C-Cyaikyl, Ci-Cralkoxy, halogen and trifluoromethyt and where R4 additionally is hydrogen; or R4 and R5 together represent Cg" Cealkylene; and R" represents hydrogen; or R" and R" independently represent d-C/alky in free form or in form of a pharmaceuticalJy acceptable acid addition salt. The compounds of the invention may be prepared e.g. by a process which comprises coupling a reactive (2-cyanopyrrolidino)carbonylmethy1ene compound with an appropriate substituted amine; more particularly, for the preparation of the compounds of formula I, it comprises reacting a compound of formula il The compounds of the invention may be isolated from the reaction mixture and purified in conventional manner, e.g. by chromatography. step 1 involves the reaction of the pyrrolidine of fomiuia iV with a slight molar excess of a haloacetylhalide such as bromoacetylbromide or chioroacetylchioride and a base such as potassium carbonate or triethyfamine. The reaction convenientfy is conduct! in the presence of an inert, organic solvent, such as tetrahydrofuran or a chlorinated, aliphatic hydrocarbon such as methylene chloride, at a temperature of from about O^to about aS^C, preferably at a temperature between about 0" and about IS^C. Step 2 concerns the dehydration of the compound of formula V, prepared in Step 1 with 1 to 2 equivalents of trifluoroacetic anhydride (TFAA). The dehydration preferably is conducted in the presence of an inert, organic solvent such as tetrahydrofuran or a chlorinated, aliphatic hydrocarbon such as methylene chloride, at a temperature of from about 0" to about as^C, preferably at a temperature between about 0" and about IS^C. Insofar as its preparation is not particulariy described herein, a compound used as starting material is known or may be prepared from known compounds in known manner o analogously to known methods or analogously to methods described in the Example. For example, the primary amine compounds of formula 111 are known and may be prepared by procedures documented in the literature, for example, Khim. -Farm. 2h. (1986 20(7), 810-15. Rnally, compounds of the invention are either obtained in the free form, or as a sal thereof if salt forming groups are present. Compounds of the invention having basic groups can be converted into acid In view of the close relationship between the free compounds and the compounds the fomi of their salts, whenever a compound is refened to in this context, a con^spondin saif is also intended, provided such is possible or appropriate under the circumstances. The compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. The instant invention also includes phannaceutical compositions, for example, use in inhibiting DPP-IV, comprising a phamiaceutically acceptable carrier or diluent and a therapeuticaily effective amount of a compound of fonnula I, or a phamiaceutically acceptable acid addition salt thereof. In still another embodiment, the instant invention provides a method of inhibiting DPP-IV comprising administering to a mammal in need of such treatment a therapeuticall] effective amount of a compound of fomula I, or a phamaceutically acceptable add addit sail thereof. In a further embodiment, the instant invention provides a method of treating conditions mediated by DPP-IV inhibition comprising administering to a mammal in need ( such treatment a therapeutically effective amount of a compound of fomiula I above, or a pharmaceuticatly acceptable acid addition salt thereof. The present invention also relates to the use of a compound according to the insts invention or a phannaceutically acceptable salt thereof e.g. for the manufacture of a medicament for the prevention or treatment of diseases or conditions associated with elevated levels of DPP-IV. As indicated above, all of the compounds of formula I, and their corresponding pharmaceutlcally acceptable acid addition salts, are useful in inhibiting DPP-IV. The abtiil of the compounds of formula t, and their corresponding pharmaceutlcally acceptable acid addition salts, to inhibit DPP-IV may be demonstrated employing the Caco-2 DPP-(V Ass£ which measures the ability of test compounds to inhibit DPP-IV activity from human coloni carcinoma cell extracts. The human colonic carcinoma cell line Caco-2 was obtained fron the American Type Culture Collection {ATCC HTB 37). Differentiation of the cells to lndu( npp-iu PYnrflRsion was accomolished as described bv Reisher. et al. in an article entitled Caco-2 protein, diluted to a final volume of 125 pi in assay buffer (25 mM Tris HCI pH 7.4 140mfw1 NaCI, 10 mM KCI, 1 % bovine serum albumin) to microliter plate wells. After a 60 min. incubation at room temperature, the reaction is initiated by adding 25pl of 1 mM substrate (H-AIanine-Proiine-pNA; pNA is p-nitroaniline). The reaction is canied out at roi temperature for 10 minutes after which time a 19 pi volume of 25% glacial acetic acid Is added to stop the reaction. Test compounds are typically added as 30 p) additions and tF assay buffer volume is reduced to 95 pi. A standard curve of free p-nitroaniline is generated using 0-500 pM solutions of free pNA in assay buffer. The curve generated is linear and is used for interpolation of substrate consumption (catalytic activity in nmoles substrate cleaved /min). The endpoint is detemined by measuring absorbanco at 405 nr in a Molecular Devices UV Max microtiter plate reader. The potency of the test compounds as DPP-iV inhibitors, expressed as ICso, Is calculated from 8-point, dose-response curves using a 4-parameter logistic function. The following IC50 was obtained: The ability of the compounds of formula I, and their con-esponding phamiaceutical acceptable acid addition salts, to inhibit DPP-IV may also be demonstrated by measuring the effects of test compounds on DPP-IV activity in human and rat plasma employing a modified version of the assay described by Kubota, et al. in an article entitled "Involvemei of dipeptidylpeptidase IV in an in vivo immune response" in Clin. Exp. Immunol., Vol. 89, pgs. 192-197 (1992). Briefly, 5 pi of plasma are added to 96-well flat-bottom microtiter plates (Falcon), followed by the addition of 5 pi of 80 mM MgCl2 in incubation buffer (25 mMHEPES, 140 mM NaCI, 1% RIA-grade BSA, pH 7.8). After a 60 min. incubation at rot typically added as 2 |jl additions and the assay buffer volume is reduced to 13 |jl. A fluorescence-concentration curve of free AMC is generated using 0-50 \xM solutions of Al in assay buffer. Tiie curve generated is linear and is used for interpolation of substrate consumption {catalytic activity in nmoles substrate cleaved/min). As with the previous assay, the potency of the test compounds as DPP-IV intiibitors, expressed as IC50, is calculated from 8-point, dose-response curves using a 4 parameter logistic function. The following IC50 was obtained: In view of their ability to inhibit DPP-IV, the compounds of formula I, and their corresponding pharmaceutlcally acceptable acid addition salts, are useful in treating conditions mediated by DPP-IV inhibition. Based on the above and findings in the literati it is expected that the compounds disclosed herein are useful in the treatment of conditio such as non-insulin-dependent diabetes mellitus, arthritis, obesity, allograft transplantatic and calcitonin-osteoporosis. In addition, based on the roles of glucagon-like peptides (si as GLP-1 and GLP-2) and their association with DPP-IV inhibition, it is expected that the compounds disclosed herein are useful for example, to produce a sedative or anxiolytic effect, or to attenuate post-surgical catabolic changes and homnonal responses to stress to reduce mortality and morbidity after myocardial Infarction.or in the treatment of conditf( related to the above effects which may be mediated by GLP-1 and/or GLP-2 levels. More specifically, for example, the compounds of fomiula 1, and their correspondii pharmaceutlcally acceptable acid addition salts, improve early insulin response to an oral glucose challenge and, therefore, are useful in treating non-insulin-dependent diabetes mellitus. The ability of the compounds of fom^ula I, and their corresponding pharmaceutlcally acceptable acid addition salts, to improve early insulin response to an c into groups of 8-10, and dosed orally with 10 pmol/kg of the test compounds in CMC. An oral glucose bolus of 1 g/kg was administered 30 minutes after the test compound directl into the stomach of the test animals. Blood samples, obtained at various timepoints from chronic jugular vein catheters, were analyzed for plasma glucose and immunoreactive insulin (IRt) concentrations, and plasma DPP-IV activity. Plasma insulin fevefs were assayed by a double antibody radioimmunoassay (RIA) method using a specific anti-rat Insulin antibody from Unco Research (St. Louis, MO). The RIA has a lower limit of detection of 0.5 pU/mL with Intra- and inter-assay variations of less than 5%. Data are expressed as % increase of the mean of the control animals. Upon oral administration, each of the compounds tested amplified the early insulin response which led to an improvement in glucose tolerance in the insulin resistant test animals. T?ie following rest were obtained: The precise dosage of the compounds of formula I, and their corresponding pharmaceutically acceptable acid addition salts, to be employed for treating conditions mediated by DPP-IV inhibition depends upon several factors, including the host, the natu and the severity of the condition being treated, the mode of administration and the partict compound employed. However, in general, conditions mediated by DPP-IV inhibition are effectively treated when a compound of formula I, or a con-esponding pharmaceuttcaliy acceptable acid addition salt, is administered enterally, e.g., orally, or parenteralty, e.g., intravenously, preferably orally, at a daily dosage of 0.002-5, preferably 0.02-2.5 mg/kg body weight or, for most larger primates, a daily dosage of 0.1-250, preferably 1-100 mg. typical oral dosage unit Is 0.01 -0.75 mg/kg, one to three times a day. Usually, a small do is administered initially and the dosage is gradually increased until the optimal dosage foi and, optionally, one or more other conventional pharmaceutical adjuvants and administer enterally, e.g., orally, in the form of tablets, capsules, caplets, etc. or parenterally, e.g., intravenously, in the form of sterile injectable solutions or suspensions. The enteral and parenteral compositions may be prepared by conventional means. The compounds of formula I, and their corresponding phamiaceuticalfy acceptabit acid addition salts, may be fomiuiated into enteral and parenteral phamiaceutical compositions containing an amount of the active substance that is effective for treating conditions mediated by DPP-IV inhibition, such compositions in unit dosage fonri and sue compositions comprising a phamiaceuticaily acceptable carrier. The compounds of formula I (including those of each of the subscopes thereof an each of the examples) may be administered in enantiomerically pure fomi (e.g., ee >98% preferably >99%) or together with the B enantiomer, e.g., in racemic fom. The above dosage ranges are based on the compounds of formula I (excluding the amount of the B enantiomer). The following examples show representative compounds encompassed by this invention and their synthesis. However, it should be clearly understood that they are for purposes of illustration only. A. 1-Aminoadamantane-3-ol: Sliaht modifications to the synthesis found in Khim. -Fami. Zh. (1986), 20(7), 810 ■ upon adamantylamine hydrochloride addition, slight bubbling occurs and the reaction is slightly exothermic. This bubbling, yellow solution is stin^ed at ice-water temperature for about 2 hours and then at room temperature for 30 houre. This clear, light yellow reactioi then poured into about 10Og of ice and the resulting solution is clear green-blue. The solution is placed in an ice-water Path and allowed to stir for 30 minutes. Approximately 550g of 89% pure KOH (8,74 mol) is then added In small portions over 45 minutes. During this addition, the reaction is exothemiic; reaching SOX and producing copious amounts of brown N02 gas. By the end of the addition, the reaction is thick with white solids (both product and salts). The resulting white paste is then poured onto a buchner funnel/celite pad and washed with 1.2 L of CH2CI2. The CH2CI2 layer is ttien extracted from the water layer and dried over Na2S04. The solution is then filtered and concentrated (rotovap/pump) to provide 1-aminoadamantane-3-ol as a white solid. B. 1 -Chloroacetvl-2-cvanopvrrolidin9 To a mechanically stirred sotution of 20.0g (ISO.Ommol) of chloroacetyJchloride ar 97g (0.70mmol) of potassium carbonate in 150mL of tetrahydrofuran is added a solution L-proIinamide 20.0g (ISO.Ommol) in 500 mL of tetrahydrofuran in a dropwise fashion ov( 45 minutes. This reaction is then mechanically stirred for an additional two hours at roor temperature. The reaction is then filtered to remove potassium salts and the filtrate is dr over NajSOj. The Na2S04 is then removed via fiitration and to this colorless filtrate is added trifluoroacetic anhydride (25.0mL, dSOmmol) In one portion. The reaction is the magnetically stirred for 1 hour at room temperature and the resulting clear yellow/orange solution is concentrated via rotovap. The excess trifluoroacetic anhydride is removed by adding ethyl acetate to the concentrated oi! and reconcentrating via rotovap. This remo^ operation Is perfonned three times. The resulting oil is partitioned between ethyl acetate and water. The product is thi extracted into the ethyl acetate and the aqueous layer is then washed twice with ethyl acetate. 17ie combined organic layers are then washed successively with water and brir dried over magnesium sulfate, filtered and concentrated to obtain 1 -chloroacetyl-2- To a heterogeneous solution of the title A compound (1-aminoadamantane-3-ol (5.80g,34.7mmol) in CHzCIs (68,0mL) is added 9.6g (69mmol) of KaCOg. This iieterogeneous mixture is then cooled in an ice-water bath and a solution of 3.0g (17mmc of the title B compound {1-chIoroacetyl-2-cyanopyrroItdine) dissolved in 25.0mL of CH2C!: added dropwise over a period of 30 minutes. The resulting mixture is stirred for 2 hours £ O^^C and at room temperature for 6 days. TTie reaction Is then concentrated to obtain a yellow pasty material which is purified on silica gel employing a SIMS/Blotage Rash chromatography system and a 7% solution of methanol in methylene chloride as the elue to yield the title compound in free base form as a white crystalline solid (melting point 138OC-140OC, "CNMR (ppm) = 119.59). The amino-adamantane starting materials are l The manufacture of 3.5-dimethvl-1 -adamantylamine is described in J. Med. Chem 25; 1; 1982; 51-56. The manufacture of 3-elhyl-1 -adamantylamine is described in J. Med. Chem, 25; 1982; 51-56. 3-Methoxv-1 -adamantylamine can be prepared as follows: To a stirred, ice-water chilled suspension of potassium hydride (0.6S0 gm; 5.95 mm in 15.0 ml of tetrahydofuran is added a mixture of 1-aminoadamantane-3-ol (I.OOg; 5.95 mmol) and 15.0 ml of tetrahydrofuran dropwise over 30 minutes. The resulting mixture is then stin^ed for an addition 30 minutes and iodomethane (0.370 ml; 5.95 mmol) is then added dropwise over one minute. The resulting opaque white reaction is then stirred at room temperature for 18 hours. The mixture is then diluted with 50 ml of methylene chlor and filtered to remove the inorganic impurities. The filtrate is then concentrated and purif on silica gel employing a SIMS/Biotage apparatus and 19% methanol and 1% ammonium hydroxide tn methylene chloride as eJuent to yie\d S-methoxy-l-adamantylamine as an opaque oil. Synthesis of 3-[f(t9rtbutylamino)carbonyl]oxyM-aminoadamantane: To a mixture of 1-aminoadamantane-3-oi (5.00 g; 30.0 mmol) and potassium carbonate (6.20 g; 45 mmol) in 150 ml of tetrahydrofuran is added benzylchlorofonnate (4.70 g, 33.0 mmol) in dropwise fashion over a 10 minute period. The mixture is then stin at room temperature for 2 h and then partitioned between ethyl acetate and water. The product is then extracted Into the ethyl acetate and the aqueous layer Is Hashed twice wft ethyl acetate (100 ml). The combined organic layers are then washed successively with 100 ml of aqueous 2 N sodium hydroxide, water and brine, dried over sodium sulfate, f iitfimd and concentrated ^rotovao/oumD) to provide 1 -benzvlcarbamovladamantane-S-oi i for 18 hours, concentrated (rotovap) and purified on silica gel employing a SIMS/Biotage apparatus and 20% ethyl acetate in hexane as eluent to yield 3-{[(tertbutylamino)carboni oxy]-1-benzylcarbamoyladamantane as a white solid in quantitative yield. To a mixture of 3-[[(tertbutylamino)carbonyl]oxy]-1 -benzylcarbamoyladamantane (1 g, 3.75 mmol) and 10% palladium on carbon (400 mg) in ethanol (150 ml) in a 1-liter pan hydrogenation flask is added hydrogen (50 psi). This opaque black mixture is then shaki for 24 h. The reaction is then filtered through celite to remove the palladium catalyst and concentrated (rotovap/pump) to provide 3-[[(tertbutyIamino)carbonyl]oxy>1 -aminoadamantane as a clear oil in 99% yield. The procedure for the synthesis of 4-[f[(methoxyphenvl)amino]carbonvnoxv1-1-aminoadamantane is essentially the procedure of 3-[[(tertbutylamino)carbonylIoxy]-1 -aminoadamantane except in the second step where an equivalent of 4-methoxyphenyl isocyanate replaces tert-butylisocyanate, 1,2-dichloroethane is used as solvent instead o methylene chloride and the reaction is stirred at 50^0 for 18 hours. The final amine intermediate Is provided as an oil. The procedure for the synthesis of 3-ff/phenv)amino)carf3onvl]oxv| -1-aminoadamantane is essentially the procedure of 3-[[(tertbutylamino)carbonyl]oxy]-1 -aminoadamantane except in the second step where an equivalent of phenyl isocyanate replaces the tert-butyllsocyanate, 1,2Kiichloroethane is used as solvent instead of methylene chloride and the reaction is stirred at SO^C for 18 hours. The final amine intermediate is provided as a clear oil. The procedure to make 2-aminoadamantane-5-ol is the same as in Example 1 exc£ that the starting material is 2-aminoadamantane instead of 1-aminoadamantane. The procedure for the synthesis of the nucleophile 3-acetoxv-l -aminoadamantane i essentially the procedure of 3-[[(tertbutylamino)cari3onyl1oxy]-1 -aminoadamantane excep tnr a clanHarH ar-MlaWnn nf 1-hnn7v[rarhnmnvl!4HnmantAne-3-ol Usina 1.2 BO of acetvl The procedure for the synthesis of 3-ffffdlisopropvl)amino]carfJonvnoxv]-1-amino¬adamantane is essentially the procedure of 3-[[(tertbutylamino)carbonyI]oxy]-1-aminoadamantane except in the second step where an equh/alent of diisopropylcarbamc chloride replaces the tert-butyiisocyanate, 1,2-dichloroethane is used as solvent instead methylene chloride and the reaction is stirred at BS^C for 18 hours. The final amine intermediate is provided as a gray solid. The procedure for the synthesis of S-ffffcvclohexyhaminolcartonvnoxyl-l-aminoadamantane is essentially the procedure of 3-[[(lertbutyiamino)carbonyI]oxy]-1-aminoadamantane except in the second step where an equivalent of cyclohexyiisocyana replaces the tert-butyiisocyanate, 1,2-dichloroethane is used as solvent instead of methylene chloride and the reaction is stirred at SO^C for 18 hours. The final amine intemnedlate is provided as a thick clear oil. The procedure to make 3-ethoxv-1 -adamantvlamJne (a clear oil) is the same as for methoxy-1-adamantylamine except that iodoethane (1.3 equivalent) is used instead of iodomethane. Fonnulation Example: Tablets, each containing 50 mg of active ingredient, for example, (S)1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-pyn"olidine, can be prepared as fo/lowfs; Comoosition /for 10,000 tablets) Active ingredient 500.0 g Lactose 500.0 g Potato starch 352.0 g Gelatin 8.0 g Tairt fin On The active ingredient is mixed with the lactose and 292 g of potato starch, and the mixtui is moistened using an alcoholic solution of the gelatin and granulated by means of a siev After drying, the remainder of the potato starch, the talc, the magnesium stearate and thi highly disperse silica are admixed and the rrixture is compressed to give tablets of weigh 145.0 mg each and active ingredient content 50.0 mg which, if desired, can be provided with breaking notches for finer adjustment of the dose. WE CLAIM: 1. A compound of formula (lA) or (IB) C0-0-, where R4 and R5 independently are Ci-C7alkyl or phenyl which is unsubstituted or substituted by a substitiient selected from C1-C7 alkyl, C,-C7alkoxy, halogen and trifluoromethyl and where R4 additionally is hydrogen; or R4 and R^ together represent CrCs^lkylcnc; and R" represents hydrogen; or R" and R" independently represent C|-C7alkyl; in free form or in form of a pharmaceutic ally acceptable acid addition salt. 2. The compound as claimed in claim 1 of formula (lA) or (IB) selected from the group consisting of pyrrolidine, l-[f(3,5-dimethyl-l-adiimanlyl)amino]-acetyl]-2-cyano-, (S)-; pyrrolidine, l-[[(3-ethyl-l-adamantyI)amino]-acelyl]-2-cyano-, (S)-; pyrrolidine, ]-f[(3-methoxy-l-adaniantyl)amino]-acetyl]-2-cyano-, (S)-; pyrrolidine, l-[[[3-[[(t-butylamino)carbonyl]oxy]-l-adamantyl)amino]-acetyl]- 2-cyano-, (S)-; pyrrolidine, l-[[[3-[[[(4-methoxyphenyl)amino]-carbonyI]oxy]-i-adamantyl) amino]-acetyl]-2-cyano-, (S)-; pyrrolidine, 1 -[[[3-[[(phenylamino)carbonyl]oxy]-1 - adamantyI)amino]-acetyl]- 2-cyano-, (S)-; pyrrolidine, 1 -[[(5-hydroxy-2-adamantyI)amino]-acetyl]-2-cyano-, (S)-; pyrrolidine, l-[[(3-acetyloxy-!-adamantyl)amino]-acelyl]-2-cyano-, (S)-; pyrrolidine, ]-[[[3-[[[(diisopropyl)amino)carbonyl]oxy]-l-adamantyl)amino]- acetyl]-2-cyano-, (S)-; pyrrolidine, l-[[[3-[[[(cyclohexyl)amino]carbonyl]oxy]-l-adamantyl)amino]- acelyl]-2-cyano-, (S)-; and pyrrolidine, l-[[(3-ethoxy-l-adamanty!)amino]-acetyl]-2-cyano-, (S)-; or, in each case, a pharmaceulically acceptable acid addition salt thereof. 3. Pyrrolidine, l-[(3-hydroxy-l-adamantyl)amino]acetyl-2-cyano-, (S), as claimed m claim 1, or a pharmaceutically acceptable salt thereof. 4. A pharmaceutical composition comprising a compound as claimed in any one of claims I to 3, in free forni or in pharmaceutically acceptable acid addition salt form, together with at least one pharmaceutically acceptable carrier or diluent, 5. A compound of formula (lA) or (IB) as herein described and exemplified.

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