WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) 1“te1‘nati0n31 Patent Classification 6 3
`
`C071) 207/00, 401/00, C07K 5/00 (43) International Publication Date:
`
`('11) International Publication Number:
`
`W0 98/
`
`14 May 1998 (1-1.05.98)
`
`(21) International Application Number:
`
`PCT/EP97/06125
`
`(22) International Filing Date:
`
`5 November 1997 (0511.97)
`
`(30) Priority Data:
`08/746,295
`
`7 November 1996 (07.1 1.96)
`
`US
`
`(71) Applicant (for all designated States except US): NOVARTIS
`AG [CII/CH]; Schwarzwaldallee 215, CH-4058 Basel (CH).
`
`(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR,
`BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GE, GE,
`GH, HU, ID. IL, IS, JP. KE, KG, KP, KR, KZ, LC, LK,
`LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO,
`NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR,
`TI‘, UA, UG, US, UZ, VN, YU, ZW, ARIPO patent (Gil,
`KE, LS, MW, SD, SZ, UG, ZW), Eurasian patent (AM, AZ,
`BY, KG, KZ, MD, RU, TJ, TM), European patent (AT, BE,
`CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL,
`PT, SE), OAPI patent (BF, BJ. CF, CG, CI. CM, GA. GN.
`ML, MR, NE, SN, TD, TG).
`
`(72) Inventor; and
`(for US only): VILLHAUER, Edwin, Published
`(75) Inventor/Applicant
`Bernard [US/US];
`20 Dorothy Drive, Morristown, NJ
`Without international Search report and to be republished
`07960 (US).
`upon receipt nfthar report.
`
`(74) Agent: ROTH, Bernhard, M.; Novartis AG, Patent— und
`Markenabteilung, Lichtstrasse 35, CH—-~4002 Basel (CH).
`
`(54) Title: N—S UBS'l‘l'l'LI'l‘ED 2—CYAN OPYRROLIDIN ES
`
`(57) Abstract
`
`the
`N—(N’—substituted glycyl)~2—cyanopyrrolidines, e.g.
`compounds of formula (I) wherein R has various significances, are
`novel. They inhibit DPP—IV (dipeptidyl—peptidase——IV) activity.
`They are therefore indicated for use as pharmaceuticals in inhibiting
`DPP-IV and in the treatment of conditions mediated by DPP-IV,
`such as non—insulin—dependent diabetes mellitus, arthritis. obesity,
`osteoporosis and further conditions of impaired glucose tolerance.
`
`H
`
`\
`
`/
`R
`
`N
`
`O
`
`“\\
`‘
`
`EXHIBIT
`
`Ex. 1 008
`
`Ex. 1008
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:27)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:3)(cid:82)(cid:73)(cid:3)(cid:21)(cid:26)
`Sun-Amneal-lPR2016-O1104- Ex. 1008, p. 1 of 27
`
`

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`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`ES
`Fl
`FR
`GA
`GB
`GE
`GII
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
`Yugoslavia
`Zimbabwe
`
`SI
`SK
`SN
`SZ
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UG
`US
`UZ
`VN
`YU
`ZW
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`R0
`RU
`SD
`SE
`SG
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`BF‘.
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`CU
`CZ
`DE
`DK
`
`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Cole d’Ivoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`Spain
`Finland
`Fl“zlll(Jt:
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People’s
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`KR
`KZ
`LC
`Ll
`LK
`LR
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:27)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:21)(cid:3)(cid:82)(cid:73)(cid:3)(cid:21)(cid:26)
`Sun-Amneal-lPR2016-01104- Ex. 1008, p. 2 of 27
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`

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`W0 98/ 19998
`
`PCT/EP97/06125 N
`
`N-SUBSTITUTED 2-CYANOPYRROLIDINES
`
`Field
`
`The present invention relates to N-substituted 2—cyanopyrrolidines. More particularly,
`
`it provides novel N-glycyl-2—cyanopyrrolidine derivatives.
`
`Background
`
`Dipeptidyl peptidase~IV (DPP-IV) is a serine protease which cleaves N—terminal
`
`dipeptides from a peptide chain containing, preferably, a proline residue in the penultimate
`
`position. Although the biological role of DPP-IV in mammalian systems has not been
`
`completely established, it is believed to play an important role in neuropeptide metabolism,
`
`T-cell activation, attachment of cancer cells to the endothelium and the entry of HIV into
`
`lymphoid cells. DPP-IV is responsible for inactivating glucagon—like peptide-1 (GLP-1).
`
`More particularly, DPP~IV cleaves the amino—terminal His~Ala dipeptide of GLP—l, generating
`
`a GLP—l receptor antagonist, and thereby shortens the physiological response to GLP—l. Since
`
`the half-life for DPP~IV cleavage is much shorter than the half-life for removal of GLP-1 from
`
`circulation, a significant increase in GLP~1 bioactivity (5- to 10-fold) is anticipated from
`
`DPP-IV inhibition. Since GLP-1 is a major stimulator of pancreatic insulin secretion and has
`
`direct beneficial effects on glucose disposal, DPP-TV inhibition appears to represent an
`
`attractive approach for treating non-insulin—dependent diabetes mellitus (NIDDM).
`
`Although a number of DPP—IV inhibitors have been described, all have limitations
`
`relating to potency, stability or toxicity. Accordingly, a great need exists for novel DPP~IV
`
`inhibitors which are useful in treating conditions mediated by DPP~IV inhibition and which do
`
`not suffer from the above-mentioned limitations.
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:27)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:22)(cid:3)(cid:82)(cid:73)(cid:3)(cid:21)(cid:26)
`Sun-Amneal-lPR2016-01104- Ex. 1008, p. 3 of 27
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`W0 98/ 19998
`
`PCT/EP97/06125 ,.
`
`Summary of the invention
`
`The invention provides novel N-(N’-substituted glycyl)-2-cyanopyrrolidines which are
`
`effective as DPP~IV inhibitors in treating conditions mediated by DPP-IV. It also concerns
`
`corresponding pharmaceutical compositions, a process for their preparation, a method of
`
`inhibiting DPP—IV comprising administering to a patient in need of such treatment a
`
`therapeutically effective amount thereof, the compounds for use as a pharmaceutical, and their
`
`use in a process for the preparation of a medicament for treating a condition mediated
`
`by DPP-IV.
`
`Detailed description
`
`The invention concerns N-(N’—substituted glycyl)-2—cyanopyrrolidines, hereinafter
`
`briefly named "the compounds of the invention"; more particularly, it concerns compounds
`
`of formula I:
`
`wherein R is:
`
`a) R1R1,N(CH2),,,- wherein
`
`R1 is a pyridinyl or pyrimidiny] moiety optionally mono— or independently
`
`disubstituted with (C1.4)a1ky1, (C1.4)alkoxy, halogen, trifluoromethyl,
`
`cyano or nitro; or phenyl optionally mono— or independently disubstituted
`
`with (Ci.4)alkyl, (C..4)alkoxy or halogen;
`
`R13 is hydrogen or (C1.g)a1kyl; and
`
`m is 2 or 3;
`
`b) (C3.1;)cycloalkyl optionally monosubstituted in the l—position with (C1.3)hydroxyalkyl;
`
`c) R2(CH2).,- wherein either
`
`R; is phenyl optionally mono— or independently di— or independently trisubstituted
`
`with (C1.4)alkyl, (CM)alkoxy, halogen or phenylthio optionally monosubstituted
`
`in the phenyl ring with hydroxymethyl; or is (C1-g)a1ky1; a [3.1.1]bicyclic
`
`carbocyclic moiety optionally mono— or plurisubstituted with (C1.g)a1kyl;
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:27)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:23)(cid:3)(cid:82)(cid:73)(cid:3)(cid:21)(cid:26)
`Sun-Amneal-lPR2016-01104- Ex. 1008, p. 4 of 27
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`

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`WO 98119998
`
`PCT/EP97/06125 ..
`
`.3-
`
`a pyridinyl or naphthyl moiety optionally mono- or independently disubstituted
`
`with (C14)alky1, (C1.4)allcoxy or halogen; cyclohexene; or adamantyl; and
`
`n is 1 to 3; or
`
`R2 is phenoxy optionally mono- or independently disubstituted with (CM)alkyl,
`
`(CH)alkoxy or halogen; and
`
`n is 2 or 3;
`
`d) (R3)2CH(CH2)2- wherein each R3 independently is phenyl optionally mono- or
`
`independently disubstituted with (CM)alkyl,
`
`(CM)alkoxy or halogen;
`
`e) R4(CH2),,- wherein R4 is 2-oxopyrrolidinyl or (C2.4)alkoxy and
`
`p is 2 to 4;
`
`f) isopropyl optionally monosubstituted in 1-position with (C,.3)hydroxyalkyl;
`
`g) R5 wherein R5 is:
`
`indanyl; a pyrrolidinyl or piperidinyl moiety optionally substituted with
`
`benzyl; a [2.2.1]— or [3.l.1]bicyclic carbocyclic moiety optionally mono- or
`
`plurisubstituted with (C,-g)alkyl; adamantyl; or (C1.g)alky1 optionally mono- or
`
`independently plurisubstituted with hydroxy, hydroxymethyl or phenyl optionally mono-
`
`or independently disubstituted with (CM)a1kyl, (C1_4)alkoxy or halogen;
`
`in free form or in acid addition salt form.
`
`The compounds of formula I can exist in free form or in acid addition salt form. Salt
`
`forms may be recovered from the free form in known manner and vice—versa. Acid addition
`
`salts may e.g. be those of pharmaceutically acceptable organic or inorganic acids. 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 exist in the form of optically active isomers or
`
`diastereoisomers and can be separated and recovered by conventional techniques, such as
`
`chromatography.
`
`"Alkyl" and "alkoxy" are either straight or branched chain, of which examples of the
`
`latter are isopropyl and tert-butyl.
`
`R preferably is a), b) or e) as defined above. R1 preferably is a pyridinyl or pyrimidinyl
`
`moiety optionally substituted as defined above. R1,, preferably is hydrogen. R2 preferably is
`
`phenyl optionally substituted as defined above. R3 preferably is unsubstituted phenyl.
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:27)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:24)(cid:3)(cid:82)(cid:73)(cid:3)(cid:21)(cid:26)
`Sun-Amneal-lPR2016-01104- Ex. 1008, p. 5 of 27
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`W0 98/19998
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`PCT/EP97/06125 ,
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`-4-
`
`R4 preferably is alkoxy as defined above. R5 preferably is optionally substituted alkyl as defined
`
`above.
`
`in preferably is 2. n preferably is 1 or 2, especially 2. p preferably is 2 or 3,
`
`especially 3.
`
`Pyridinyl preferably is pyridin-2-yl; it preferably is unsubstituted or monosubstituted,
`
`preferably in 5-position. Pyrirnidinyl preferably is pyrimidin-2-yl. It preferably is unsubstituted
`
`or monosubstituted, preferably in 4-position. Preferred as substitutents for pyridinyl and
`
`pyrimidinyl are halogen, cyano and nitro, especially chlorine.
`
`When it is substituted, phenyl preferably is monosubstituted; it preferably is substituted
`
`with halogen, preferably chlorine, or methoxy. It preferably is substituted in 2~, 4» and/or
`
`5-position, especially in 4—position.
`
`(C3_12)cycloalky] preferably is cyclopentyl or cyclohexyl. When it is substituted, it
`
`preferably is substituted with hydroxymethyl. (C1.4)alkoxy preferably is of l or 2 carbon
`
`atoms, it especially is rnethoxy. (C2.4)alkoxy preferably is of 3 carbon atoms, it especially is
`
`isopropoxy. Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or
`
`bromine, especially chlorine. (C1.g)alkyl preferably is of 1 to 6, preferably 1 to 4 or 3 to 5,
`
`especially of 2 or 3 carbon atoms, or methyl. (CM) alkyl preferably is methyl or ethyl,
`
`especially methyl. (C1_3)hydroxyalkyl preferably is hydroxymethyl.
`
`A [3.1.1]bicyclic carbocyclic moiety optionally substituted as defined above preferably
`
`is bicyclo[3.1.l]hept—2-yl optionally disubstituted in 6-position with methyl, or
`
`bicyclo[3.l.l]hept-3—yl optionally trisubstituted with one methyl in 2-position and two methyl
`groups in 6~position. A [2.2.l]bicyclic carbocyclic moiety optionally substituted as defined
`
`above preferably is bicyclo[2.2.1]hept-2-yl.
`
`Naphthyl preferably is 1-naphthyl. Cyclohexene preferably is cyclohex—l—en—1-yl.
`
`Adamantyl preferably is 1- or 2—adamantyl.
`
`A pyrrolidinyl or piperidinyl moiety optionally substituted as defined above preferably is
`
`pyrrolidin-3-yl or piperidin-4-yl. When it is substituted it preferably is N-substituted.
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:27)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:25)(cid:3)(cid:82)(cid:73)(cid:3)(cid:21)(cid:26)
`Sun-Amneal-lPR2016-01104- Ex. 1008, p. 6 of 27
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`

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`W0 98/19998
`
`PCT/EP97/06125 ,_
`
`-5-
`
`A preferred group of compounds of the invention is the compounds of formula I
`
`wherein R is R’ (compounds Ia), whereby R’ is:
`
`- R,’NH(CH2)2- wherein R1’ is pyridinyl optionally mono- or independently disubstituted with
`
`halogen, trifluoromethyl, cyano or nitro; or unsubstituted
`
`pyrimidinyl;
`
`- (C3.7)cycloalkyl optionally monosubstituted in l-position with (C,-3)hydroxyalkyl;
`
`~ R4’(CH2)3- wherein R4’ is (C2.4)a1koxy; or
`
`- R5, wherein R5 is as defined above;
`
`in free form or in acid addition salt form.
`
`More preferred compounds of the invention are those compounds of formula I wherein
`
`R is R-" (compounds lb), whereby R" is:
`
`- R."NI~I(CI~l2)g- wherein R1" is pyridinyl mono» or independently disubstituted with halogen,
`
`trifluoromethyl, cyano or nitro;
`
`-
`
`(C4.(,)cyc:loa1ky1 monosubstituted in l-position with (C1.3)hydroxyalky1;
`
`- R4’(CH2)3— wherein R4’ is as defined above; or
`
`- R5’ wherein R5’ is a [2.2.1]— or [3.l.1]bicyclic carbocyclic moiety optionally mono— or
`
`plurisubstituted with (C..g)alky1; or adamantyl;
`
`in free form or in acid addition salt form.
`
`Even more preferred compounds of the invention are the compounds of formula I wherein
`
`R is R"’ (compounds Ic), whereby R"’ is:
`
`- R,"NH(CH2)2- wherein R," is as defined above;
`
`-
`
`(C4_6)cycloa1kyl monosubstituted in 1~position with hydroxymethyl;
`
`- R4’(CH2)3— wherein R4’ is as defined above; or
`
`- R5" wherein R5" is adamantyl;
`
`in free form or in acid addition salt form.
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:27)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:26)(cid:3)(cid:82)(cid:73)(cid:3)(cid:21)(cid:26)
`Sun-Amneal-lPR2016-01104- Ex. 1008, p. 7 of 27
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`

`
`WO 98119998
`
`PCT/EP97/06125 ,_
`
`-5-
`
`A further group of compounds of the invention is compounds Ip, wherein R is R”,
`
`which is:
`
`a) R1"NH(CH2)2— wherein R.” is a pyridinyl or pyrimidinyl moiety optionally mono— or
`
`independently disubstituted with halogen, trifluoromethyl,
`
`cyano or nitro;
`
`b) (C3-7)cycloa1kyl optionally monosubstituted in 1-position with (C1.3)hydroxyalky1;
`
`c) R2"(CH2)2- wherein R2” is phenyl optionally mono— or independently di- or independently
`
`d) (R3")2CH(CH2)2- wherein each R3” independently is phenyl optionally monosubstituted with
`
`trisubstituted with halogen or (C1-3)a1koxy;
`
`halogen or (C1-3)alkoxy;
`
`e) R4(CH2)3— wherein R4 is as defined above; or
`
`f) isopropyl optionally monosubstituted in 1~position with (C1.3)hydroxyalkyl;
`
`in free form or in pharmaceutically acceptable acid addition salt form.
`
`A further group of compounds of the invention is compounds Is, wherein R is R‘,
`
`which is:
`
`a) RlsRlaS(CH2)nu' wherein Rf is pyridinyl optionally mono— or independently disubstituted
`
`with chlorine, trifluoromethyl, cyano or nitro; pyrimidinyl
`
`optionally monosubstituted with chlorine or trifluoromethyl;
`
`or phenyl;
`
`Rm‘ is hydrogen or methyl; and
`
`ms is 2 or 3;
`
`b) (C3.12)cycloall(yl optionally monosubstituted in 1-position with hydroxymethyl;
`
`c) Rg‘(CH2)m- wherein either
`
`R25 is phenyl optionally mono— or independently di- or independently
`
`trisubstituted with halogen, alkoxy of 1 or 2 carbon atoms or
`
`phenylthio monosubstituted in the phenyl ring with hydroxymethyl;
`
`(C 1 .o)a1kyl; 6,6—diInethy1bicyclo[3.l .l]hept-2—yl; pyridinyl;
`
`naphthyl; cyclohexene; or adamantyl; and ns is 1 to 3; or
`
`R25 is phenoxy; and ns is 2;
`
`d) (3,3—dipheny1)propyl;
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:27)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:27)(cid:3)(cid:82)(cid:73)(cid:3)(cid:21)(cid:26)
`Sun-Amneal-lPR2016-01104- Ex. 1008, p. 8 of 27
`
`

`
`W0 98/19998
`
`I
`
`PCT/EP97/06125 M
`
`-7-
`
`e) R4S(CH2)ps wherein R45 is 2-oxopyrrolidin-1~yl or isopropoxy and
`
`ps is 2 or 3;
`
`D isopropyl optionally monosubstituted in 1-position with hydroxymethyl;
`
`g) R5‘ wherein R5‘ is:
`
`indanyl; a pyrrolidinyl or pipcridinyl moiety optionally N~substituted
`
`with benzyl; bicyclo[2.2.1]hept-2-yl; 2,6,6-trimethylbicyclo—
`
`[3.1.1]hept-3~yl; adamantyl; or (C1.g)alkyl optionally mono- or
`
`independently disubstituted with hydroxy, hydroxymethyl or phenyl;
`
`in free form or in acid addition salt form.
`
`The compounds of the invention may be prepared by a process which comprises
`
`coupling a reactive (2-cyanopyrro1idino)carbonylmethylene compound with an appropriate
`
`substituted amine; more particularly, for the preparation of the compounds of formulal it
`
`comprises reacting a compound of formula II
`
`11
`
`“\<~CN
`
`0 H
`
`X\/(RN:
`
`wherein X is a reactive group,
`
`with a compound of formula III
`
`wherein R is as defined above,
`
`NHZR
`
`III
`
`and recovering the resultant compound of formula I in free form or in acid addition salt form.
`
`X preferably is a halogen such as bromine, chlorine or iodine.
`
`The process of the invention may be effected in conventional manner.
`
`The compound of formula II is preferably reacted with at least 3 equivalents of a
`
`primary amine of formula III. The reaction is conveniently conducted in the presence of an
`
`inert, organic solvent, preferably a cyclic ether such as tetrahydrofuran. The temperature
`
`preferably is of from about 0° to about 35“C, preferably between about 0° and about 25°C.
`
`The compounds of the invention may be isolated from the reaction mixture and purified
`
`in conventional manner, e.g. by chromatography.
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:27)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:28)(cid:3)(cid:82)(cid:73)(cid:3)(cid:21)(cid:26)
`Sun-Amneal-lPR2016-01104- Ex. 1008, p. 9 of 27
`
`

`
`WO 98/19998
`
`PCT/EP97/06125 AU‘
`
`-3-
`
`The starting materials may also be prepared in conventional manner.
`
`The compounds of formula II may e. g. be prepared by the following two—step reaction
`
`scheme:
`
`STEP 1
`
`
`STEP 2
`
`ii:
`o‘ NH2
`rm: 3
`
`X
`
`E
`\/Cx X
`Et3N= DMAP
`
`o
`II
`
`X \/C\
`
`i’
`__:~
`\N1—12
`]
`
`'
`
`N
`
`IV
`
`V
`
`TFAA
`(at least 2 eq.)
`
`H
`
`Step 1 involves the reaction of the pyrrolidine of formula IV with a slight molar excess
`
`of a haloacetylhalide such as bromoacetylbromide or chloroacetylchloride and triethylamine
`
`and a catalytic amount of dimethylaminopyridine (DMAP). The reaction conveniently is
`
`conducted in the presence of an inert, organic solvent, preferably a chlorinated, aliphatic
`
`hydrocarbon such as methylene chloride, at a temperature of from about 0° to about 25°C,
`
`preferably at a temperature between about 0° and about 15°C.
`
`Step 2 concerns the dehydration of the compound of formula V, prepared in Step 1,
`
`with at least 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
`
`25°C, preferably at a temperature between about 0° and about 15°C.
`
`Insofar as its preparation is not particularly described herein, a compound used as
`
`starting material is known or may be prepared from known compounds in known manner or
`
`analogously to known methods or analogously to methods described in the Examples.
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:27)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:19)(cid:3)(cid:82)(cid:73)(cid:3)(cid:21)(cid:26)
`Sun-Amneal-lPR2016-01104- Ex. 1008, p. 10 of 27
`
`

`
`WO 98/19998
`
`PCT/EP97/06125 -
`
`-9-
`
`The following Examples illustrate the invention. All temperatures are in degrees
`
`Celsius.
`
` Example 1: 1- 2-
`
`1 S Q-pyrrolidine
`
`To a 500 ml flask is added 16.6 g of 2~[(5-chloropyridin-2-yl)amino]ethylamine and
`
`100 ml of tetrahydrofuran and the mixture is cooled in an ice bath. To the cooled mixture is
`
`added 7.0 g of (2-cyanopyrrolidino)carbonylmethylene-(S)-bromide dissolved in 30 ml of
`
`tetrahydrofuran. The resultant mixture is stirred for 2 hours at 0°, the solvent is removed by
`
`rotovaping and the mixture is partitioned between ethyl acetate and water. The product is then
`
`extracted into the ethyl acetate layer and the aqueous layer is then washed twice with ethyl
`
`acetate. The combined organic layers are washed successively with water and brine, dried over
`
`sodium sulfate and concentrated to obtain the desired free base compound in crude form. The
`
`crude form is then purified on silica gel employing a mixture of 5% methanol in methylene
`
`chloride as the eluent to yield the title compound in free base form as a light brown oil.
`
`After dissolving the free base in 30 ml of dry tetrahydrofuran, hydrogen chloride gas
`
`is bubbled into the solution for five seconds. The off-white precipitate that forms is filtered,
`
`washed with dry tetrahydrofuran and the solvent is removed by high vacuum pumping to
`
`obtain the title compound in dihydrochloride acid addition salt form (off—white solid;
`
`m.p. 265°—267°; NMR: see * at bottom of Table hereunder).
`
`The starting material is obtained as follows:
`
`a) 22.37 g of (S)-2-carbamoylpyrrolidine, 30.1 ml of triethylamine and 30.0 mg of
`
`dimethylaminopyridine (DMAP) are dissolved in 200 ml of methylene chloride and the solution
`
`is then added, dropwise, to an ice—cold solution of 18.8 ml of bromoacetylbromide in 192 ml
`of methylene chloride, over a period of 60 minutes under a calcium sulfate drying tube. The
`
`resultant solution is stirred for 2 hours at ice—water temperature under a calcium sulfate drying
`
`tube, then poured into 3.5 liters of ethyl acetate. The resultant precipitate is filtered, washed
`
`with ethyl acetate, and the filtrate is concentrated to obtain (2-carbamoylpyrrolidino)-
`
`carbonylmethylene-(S)-bromide (hard yellow taffy).
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:27)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:20)(cid:3)(cid:82)(cid:73)(cid:3)(cid:21)(cid:26)
`Sun-Amneal-lPR2016-01104- Ex. 1008, p. 11 of 27
`
`

`
`W0 98/ 19998
`
`PCT/EP97/06125 ,
`
`- 10-
`
`b) 50.0 g of the bromide compound prepared in a) above is dissolved in 300 ml of methylene
`
`chloride and the solution is cooled in an ice water bath under a calcium sulfate drying tube.
`
`The cooled solution is then poured into 60.2 ml of trifluoroacetic anhydride over a 2 minute
`
`period, the resultant solution is stirred at ice-water temperature under a calcium sulfate drying
`
`tube for 4 hours, and partitioned between methylene chloride and saturated aqueous sodium
`
`bicarbonate. The product is extracted into the methylene chloride layer and the aqueous layer
`
`is washed twice with methylene chloride. The combined organic
`
`layers are washed successively with water and brine and then dried over sodium sulfate. The
`
`solution is filtered and the solvent is removed by rotovaping and high vacuum pumping to
`
`obtain (2-cyanopyrrolidino)carbonylmethylene-(S)-bromide (dark yellow solid).
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:27)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:21)(cid:3)(cid:82)(cid:73)(cid:3)(cid:21)(cid:26)
`Sun-Amneal-lPR2016-01104- Ex. 1008, p. 12 of 27
`
`

`
`The following compounds of the invention, of formula I, are obtained in analogous manner by reacting a corresponding compound of
`
`formula H with a corresponding compound of formula III (in the following Table, where only an acid addition salt form of a compound of the
`
`invention is mentioned, the compound is recovered from the free base without isolation thereof):
`
`Example
`No.
`
`Form
`
`Analogously Characterization data
`to Ex. No.
`
`DIN
`
`2-[(5-CF3-pyridin-2-yl)ami11o]ethyI
`2-[(5-cyanopyridin-2-yl)amino]ethyl
`
`2-[(pyrimidin-2-yl)amino]ethy|
`(1-bydroxymethyncyclopent-1-yl
`2-[(pyridin-2—yl)amino]ethyl
`2-[(4-chloropyrimidin-2-yl)amino]ethyl
`2-[(3-chloropyridim2~yl)amino]ethyl
`2-[(4-CF;-pyrimidin-2-yl)aminolethyl
`2-(2-chlorophenybethyl
`(3,3-diphenyl)propyl
`2-[(5-nitropyridin-2-yl)amino]ethyl
`2-[(3-chloro-S-CF3-pyridin-2-yl)amino]ethyl
`2-[(3-CF3-pyridim2-yl)amino]ethyl
`2-[(3,5-dichloropyridin-2-yl)amino]ethyl
`cyclopent-1-yl
`
`2-(2-bromo-4,5-dimethoxyphenyhethyl
`3-(isopropoxy)propyl
`
`b
`b
`dch
`
`b
`b
`b
`b
`b
`b
`b
`b
`
`b
`b
`b
`b
`b
`ch
`e b
`b
`
`ch
`
`1"
`
`I
`
`2”’
`12)
`2”
`2
`2
`2
`2
`2
`
`53*’
`23!”
`2”’
`2”’
`
`1
`53“
`I
`
`l
`
`golden oil; NMR*
`golden oil
`off-white precipitate, m.p. 155-157°; NMR*;
`[o<]o2°= — 77.2° (c=0.012, MeOH)
`golden oil; NMR*
`yellow solid; mp. 65-67°; NMR*
`golden oil; NMR*
`tan solid; NMR*
`golden oil; NMR*
`golden oil; NMR*
`NMR*
`NMR*
`
`bright yellow thick oil; NMR*
`golden oil; NMR*
`golden oil; NMR*
`golden oil; NMR*
`tan solid
`white solid; NMR*
`clear light yellow, thick oil; NMR*
`brown oil
`
`white solid, mp. l74—l76°; NMR*
`
`Sun-Amneal-|PR2016-01104- Ex. 1008, p. 13 of 27
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:27)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:22)(cid:3)(cid:82)(cid:73)(cid:3)(cid:21)(cid:26)
`
`«ll-
`
`86661/86OM
`
`SZI90/LGJEI/JJJJ
`
`

`
`Example
`N0.
`
`R
`
`Form
`
`Analogously Characterization data
`to Ex. No.
`
`13
`
`14
`
`15
`16
`17
`18
`19
`2o
`21
`22
`23
`24
`25
`
`26
`27
`28
`29
`30
`31
`32
`33
`
`b
`ch
`b
`ch
`b
`ch
`dch
`ch
`ch
`ch
`ch
`dch
`ch
`ch
`
`2—hydr0xy-1,1-dimethylethyl
`
`3-(2-oxopyrrolidin-1-yl)propyl
`
`1-hydroxymethylcyclohexyl
`2-(4-ethoxyphenyl)ethy1
`1-phenylmethyl-3-(R)-pyrrolidinyl
`2-(4-methoxypheny1)ethy1
`2-(3-me1hoxypheny1)ethy1
`(1-naphthalenyl)methyl
`3-phenylpropyl
`3-[(phenyl)(methyI)amino]propyl
`2-(3,4-dimethoxyphenyl)ethy1
`cycloheptyl
`[1S{loL,2o1(S*),5o1}]-(6,6-dimethylbicyclo[3.1.1]-
`ch
`hept-2-yl)methyl
`ch
`2-(2,S-dimethoxyphenyl)ethyl
`ch
`2-(1-cyclohexen-1-yl)ethy1
`ch
`cyclohexyl
`ch
`[1s{1a, 2a(s*),sa]]-bicycio[2.2.11hept-2-yi
`dch
`2-(2-pyridiny1)ethy1
`dch
`(2-phenylamin0)ethy1
`ch
`3,3-dimethylbutyl
`[1S[1o1,2B,3o1(S*),So1]]-2,6,6-trimethylbicyc1o[3.1.1]-
`hept-3-yl
`ch
`
`2“
`1
`25’
`1
`16)
`1
`17)
`1
`1
`1
`1
`1
`1
`1
`
`13’
`1
`1
`1
`1”
`1
`1
`1
`
`golden oil
`brown solid; NMR*
`golden oil
`tan solid; NMR*
`yellow waxy solid; mp. 93°; ‘3C—NMR: 118.1 (ppm)
`white solid; mp. 182—l84°; ”C—NMR: 121.4 (ppm)
`off-white solid; mp. 175-177°; “C-NMR: 121.5 (ppm)
`,
`white solid; m.p. 185-187“;
`’3C—NMR: 121.4 (ppm)
`light yellow solid; m.p. 172—174°; ”C—NMR: 119.25 (ppm) 5
`light yellow solid; m.p. 130—135°; “C-NMR: 119.29 (ppm)
`,
`off—white fluffy solid; BC-NMR: 1 19.26 (ppm)
`white solid; m.p. 96—98° (foams); BC-NMR: 121.6 (ppm)
`white solid; m.p. 170-172°; UC-NMR: 121.5 (ppm)
`white solid; mp. 68-70°; ”C—NMR: 121.4 (ppm)
`
`white solid; m.p. 275—279° (dec.); ”C—NMR: 119.17 (ppm)
`white fluffy so1id;m.p. 65-67°; ”C-NMR: 119.25 (ppm)
`off—white fluffy solid; m.p.162-164°; ‘3C—NMR:
`1 19.27 (ppm)
`white fluffy solid;m.p.182—184°; '3C—NMR: 119.23 (ppm)
`white solid; m.p. 93-100°; “C-NMR: 118.36 (ppm)
`white solid; mp. 95-97°; ”C-NMR: 121.5 (ppm)
`white solid; mp. 124-126“; ”C—NMR: 121.4 (ppm)
`white solid; m.p. 164—166°; “C-NMR: 121.5 (ppm)
`
`1"”
`
`white solid; m.p. s2~s4°; ”C—NMR: 121.5 (ppm)
`
`Sun-Amneal-|PR2016-01104- Ex. 1008, p. 14 of 27
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:27)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:23)(cid:3)(cid:82)(cid:73)(cid:3)(cid:21)(cid:26)
`
`86661/86OM
`
`2%’
`S
`§
`§
`5,
`1
`
`

`
`Example
`No.
`
`R
`
`Form Analogously Characterization data
`to Ex. No.
`
`34
`35
`36
`37
`38
`39
`40
`41
`42
`43
`44
`
`45
`46
`47
`48
`49
`50
`51
`52
`53
`54
`55
`56
`
`ch
`{S,S]-(1-hydroxymethyl)propyl
`{2-[(2-hydroxymethyhphenyl]thio]pheny1methyl ch
`2-(2-meth0xyphenyl)ethyl
`ch
`5-hydroxypentyl
`ch
`cyciobutyl
`ch
`2-(2,4-dichlorophenybethyl
`ch
`1-(S)-(+)-hydroxymethyl-3-methylbutyl
`ch
`[1R*,2S*]-2-hydroxy-2-phenylethyl
`ch
`2-(2-fluorophenybethyi
`ch
`cyclopropyl
`ch
`[1S[1S,2S,3S,5R]]-2,6,6-trimethylbicyclm
`[3.1.1]hept-3-yl
`(2-phenoxy)ethy1
`2-(3,5-dimethoxyphenynethyi
`1-adamamyi
`1,l,3,3-tetramethylbutyl
`2-adamantyl
`1,1-dimethylpropyl
`benzyl
`1,1-dimethylethyl
`(2-adamantyi)methy1
`2-phenylethyl
`pentyl
`butyl
`
`ch
`ch
`ch
`ch
`ch
`ch
`ch
`ch
`ch
`ch
`ch
`ch
`ch
`
`psi
`1”’
`1
`1
`1
`1
`313)
`1”’
`1
`1
`
`115)
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`
`'
`
`off-white solid; m.p. sonar; ”C-NMR: 118.2 (ppm)
`yellow solid; mp. 65—67°; ”C—NMR: 121.4 (ppm)
`off-white solid; m.p. 174-176°; ”C—NMR: 121.7 (ppm)
`sticky lighi—green solid; ‘3c—NMR: 121.67 (ppm)
`off-white solid; mp. 274—27s° (dec.); "C—NMR: 121.64 (ppm)
`white fluffy solid;m.p.1S4-156°; BC-NMR: 121.48 (ppm)
`light yeilow solid; mp. 65-66°; I3C—NMR: 117.99 (ppm)
`1
`light yellow solid; mp. 82-83°; "C-NMR: 118.35 (ppm)
`white fluffy so1id;m.p.160—162°; BC-NMR: 121.70 (ppm);
`off-white solid; m.p. 170-172°; “C-NMR: 121.62 (ppm)
`1
`
`white solid; m.p. 84—86°; BC-NMR: 121.8 (ppm)
`sticky golden solid; ”C—NMR: 121.7 (ppm)
`white fluffy solid; mp. 74-76’; ”C—NMR: 121.66 (ppm)
`white solid; m.p. 240-2422 ”C~NMR: 121.80 (ppm)
`white fluffy solid; m.p. 68-70°; 13C-NMR: 121.55 (ppm)
`off-white solid; m.p. 122-124°; ”C~NMR: 121.69 (ppm)
`white fluffy solid; m.p. 62-64°; 13C-NMR: 121.53 (ppm)
`white solid; mp. 58-60”; 13C-NMR: 121.38 (ppm)
`white solid; m.p. 226-228°; 13C-NMR: 121.55 (ppm)
`white solid; m.p. 158—160°; ”C~NMR: 121.53 (ppm)
`white solid; m.p. 275-280” (dec.)‘ ”C—NMR: 121.52 (ppm)
`white solid; mp. 176-178‘'; C-NMR: 121.67 (ppm)
`white solid; mp. 1s0—1s2°; '3C—NMR: 121.53 (ppm)
`
`86661/86OM
`
`"SZ190/L6rICI/CLDJ
`
`Sun-Amneal-|PR2016-01104- Ex. 1008, p. 15 of 27
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:27)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:24)(cid:3)(cid:82)(cid:73)(cid:3)(cid:21)(cid:26)
`
`

`
`Example
`No.
`
`R
`
`Form Analogously Characterization data
`to Ex. No.
`
`57
`58
`59
`60
`61
`62
`63
`64
`65
`as
`
`cyclododecyl
`cyclooctyl
`propyl
`ethyl
`heptyl
`hexyl
`3-{(5-cyano-2-pyridinyl)amino]pr0pyl
`1-ethylpropyl
`2,3-dihydro-1H-inden-2-yl
`1-benzylpiperidin-4-yl
`
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