(ll) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATIONTREATY (PCT)
`
`(19) World InteUectual Property
`Organization
`International Bureau
`
`1 m1a 1w1m111110 u~ m lfl~ 111111m111111m11 a11111111111111111 n11H a11 ~11 an
`
`(43) International Publication Date
`8 April 2004 (08.04.2004)
`
`PCT
`
`(10) International PUblicatioij Number.
`WO 2004/028544 Al .
`
`(51) International Patent ClassUlcatlon7:
`311575, 31/58, A61P 3106, 9/10, 25128
`
`A61K 31/57,
`
`(74) Common RepresentaUve: NOVO NORDISK A/S; Cor(cid:173)
`porate Patents, Novo All6, DK-2880 Bagsvrmt (DK).
`
`(81) Designated States (national): AB, AO, AL. AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`CZ. DE, DK, DM, DZ, EC, EE, 00, F.S, FI, GB, OD. GE,
`GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR,
`KZ, LC, LK, LR, LS, LT, LU, LV, MA. MD, MG, MK,
`MN, MW, MX, MZ, NI, NO, NZ. OM, PG, PH, PL, PT,
`RO, RU, SC, SD, SE, SG, SK, SL,. SY, TJ, TM, TN, TR,
`TI, TZ, UA, 00, US, UZ, VC, VN; YU, ZA, ZM, 'ZW.
`
`(84) Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, Tz, UG, ZM, ZW).
`Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TI, TM),
`European patent (AT, BE, BG, CH, CY, .CZ. DE, DK, EE,
`F.S, FI, FR, GB, GR, HU, IE, IT, LU, MC, NL, PT, RO,
`SE, SI, SK, TR), OAPI patent (BF, BJ, CF, CG, CL CM,
`GA, GN, GQ, GW, ML. MR, NE, SN, TD, TG).
`
`PubDshed:
`with international search repon
`before the expiration of the time limit for 'amending tlie
`claims and to be republished in the event of receipt of
`amendmenu
`
`For two-letter codes and other abbreviations, refer to the "Guid(cid:173)
`ance Notes on Codes and Abbreviationsn appearing at the begin(cid:173)
`ning of each regular issue of the PCT Gazette.
`
`(21) lntemaUonal AppUcaUon Number:
`PCT/DK2003/000619
`
`(22) Inlematlonal FIUng Date:
`23 September 2003 (23.09.2003)
`
`(25) Flllng Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(JO) Priority Data:
`PA 200201417
`
`25 September2002 (25.09.2002) DK
`
`(71) Appllcanls (for all designated Stales except US):
`NOVO NORDISK A/S [DK/DK]; Novo All6, DK-2880
`Bagsva:rd (DK). SCHERING AG [DE/DE]; MUllerstrasse
`178, 13353 Berlin (DE).
`
`-
`
`= Christian [DK/DK]; Irisvej 19, DK-3500 Va:r)\1'se (DK).
`= 13507 Berlin (DE).
`=
`--= --;;;;;;;;;;;
`--
`....-4 <
`
`(72) Inventors; and
`_
`:::=: (75) lnventors/AppDcanls (for US only): GR0NDAHL,
`
`LINDENTHAL, Bernhard [DE/DE]; Wilkestrasse 19,
`
`;;;;;;;;;;;
`
`~
`~
`lll
`00
`N
`S2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~-
`~ (54) Title: USE OF MAS-COMPOUNDS FOR TREATING DISEASF.S ASSOCIATED WITII LIPID METABOLISM
`0
`N
`(57} Abstract: Cenain sterols can be used for increasing the HDL cholesterol to non-HDL cholesterol ratio, for treatment and/or pre-
`0 vention of artherosclerosis, for treatment andlor prevention of hyper-lipidemia, for treatment of diabetic dyslipididemia·, for treatment
`:>- of hyper-<:holesterolemia, for treatment of diseases of illness related to metabolic dysfunction, for treatment of obesity or obesiws
`~ related diseases, and for the treatment of neurological diseases.
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`USE OP MAS-COMPOUNDS FOR TREATING DISEASES ASSOCIATED WZTH LZPZD METABOL:CSM
`
`1
`
`FIELD OF THE INVENTION
`
`5
`
`This .invention relates to the use of novel compounds mentioned below for Increasing the
`
`HDL cholesterol to non-HDL cholesterol ratio, for treatment and/or prevention of artheroscle(cid:173)
`rosls, for treatment and/or prevention of hyperlipidemia, for treatment of diabetic dyslipidi~
`mia, for tr~atrnent of hyper-cholesterolemla, for treatment of diseases of illness: related to ·
`metabolic dysfunction, for treatment of obesity or obesltas related diseases, and for treat~ ·
`10 ment of neurological diseases, for example, Alzheimer, associated with lipid metabolism~
`The present Invention also embraces pharmaceutical compositions and kits comprising these ·
`compounds and methods of using the compounds and their. pharmaceutical compositions, for
`example, to humans.
`
`15
`
`BACKGROUND OF THE INVENTION
`Herein the term lipoprotein covers any of the lipid-protein complexes in which lipids
`a~ transported in the blood. Llpoprotein par1icles consists of a spherical hydrophobic core of
`triglycerides or cholesteryl esters surrounded by an amphiphatic monolayer of phospholipids,
`
`cholesterol, and apolipoproteins. The expression HDL cholesterol covers high-density lipO(cid:173)
`
`p~otein and the expression non-HDL cholesterol covers the remaining lipoproteins.
`Atherosclerosis Is an eXtremely common form of arteriosclerosis in which. deposits of ·
`
`20
`
`yellowish plaques (atheromas) containing cholesterol, lipid material, and lipophages are
`formed within the intlma and inner media of large and medium-sized arteries. Arterosclerosis
`is a group of diseases characterized in thickening and loss of elasticity of arterial walls.
`Hyperlipidemla is a general term for elevated concentrations of any or all of the lip~·
`ids in the plasma, including, for example, hypertriglycerid~ma and hypercholesterolemla.
`Diabetic dyslipidemia is the typical lipid disorder associated to type II diabetes char(cid:173)
`acterized by low HOC, high LDC, and high small very dense lipid particles;
`
`25
`
`Hyper-cholesterolemia is the presence of an excess of cholesterol in the blood.
`
`Metabolic dysfunctions cover the general term describing an inappropriate reguia-
`tion of the glucose and lipid metabolism.
`
`30
`
`Alzheimer's disease· ls a progressive degenerative disease of the brain of unknown
`etiology characterized by diffuse atrophy throughout the cerebral oortex with distinctive histo-
`.
`pathology changes termed "senile plaquesn (microscopic lesions composed of fragmented
`
`.
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`axon terminals.and dendrites surrounding a core of amyloidal) and "neurofibrillaty tanglesa.
`
`(intracellular knots or clums of neurofibrils).
`
`2
`
`In. many countries, obesity is becoming a steadily increasing problem. Great effort has been
`devoted to this problem and the elevated health risk associated with obesity and metabolic
`
`· · 5
`
`imbalance. For example •. over weighty people have an increased risk of developing diabe(cid:173)
`tes~ For several subgroups of the population, for example, diabetics, overweight Increases .
`the risks in connection with the parent disease. Recent research also revealed eonnections
`.
`.
`between cholesterol metabolism and diseases of the central nervous system. For'example, it
`
`.
`
`.
`
`10
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`15
`
`is possible to delaying or preventing the onset of Alzheimer disease by cholesterol synthesis
`inhibitor5. Large portions of the health care budgets are nowadays used in obesity or obesity
`related fields. ·
`
`Many steps In the cholesterol synthesis are known. For example, the cholesterol synthesis
`proceeds via the following compounds: HMG-CoA -+ evalonic acid -+ lanosterol -+ FF-MAS
`~ T-MAS ~ desmosterol -+ cholesterol. Several. statins, for example, ·s1mvastatln, are
`known to interact on the HMG-CoA -+ evalonic acid step. The desmosterol -+ cholesterolis
`rontrolled by a st~rol A 24 reductase. .
`
`25
`
`20 One object of this Invention is to provide a medicament which can be used for Increasing the
`. HD~ cholesterol to non-HDL cholesterol ratio.
`Another object of this Invention is to provide a medicament which can be used for
`treatment and/or prevention of ait~rosclerosis.
`.
`.
`A further object of this invention is to provide a medicament which can .be used for
`treatment and/or prevention of hyper1ipldemia.
`A still further object of this invention is to provide a medicament which can be used
`for treatment of diabetic dysllpidldemia.
`A still further object of this invention is to provide a medicament which can be used
`.
`, . .
`.
`for treatment of hyper-cholesterolemia.
`A still further object of this invention is to provide a medicament which can be used
`for treatment of diseases of illness related to metabolic dysfunction.
`A still further object of this invention is to provide a medicament which can be used
`for treatment of obesity or obesitas related diseases.
`A still further object of this invention is to provide a medicament which can be used
`for treatment of neurological diseases, e. g. Alzheimer disease.
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`·Other objects of the present invention will become apparent upon reading the
`present description.
`
`3
`
`DEFINITIONS
`
`Herein, FF-MAS is 4A-dimethyl-5a..:.cholesta-8, 14,24-trlene-3(3-ol, T-MAS is 4,4-dimethyl~5a.­
`
`cholesta-8,24-dlene-3j3-ol (also designated 4,4-dimethylzymosterol), and ZK 255884 Is
`
`. (20S)-20-[(piperidin-1-yl)methyl]-4,4-dimethyl-5a-pregna-8, 14-dlen-3~1 (compound No. 2 in
`the list below).
`
`5
`
`10
`
`DESCRIPTION OF THE INVENTION
`
`· It· has now, surprisingly been found. that certain compounds hereinafter designated MAS
`
`15
`
`compound which are defined below can be used for Increasing the HDL cholesterol. to non-
`· HDL cholesterol ratio, for treatment and/or prevention of artherosclerosis, for treatment
`and/or prevention of hyperlipldemia, for treatment of diabetic dyslipididemia, for treatment of.
`
`hyper-cholesterolemia, for treatment of diseases of illness related·to metabolic dysfunction,
`
`and for treatment of obesity or obesitas related diseases.
`
`20 Herein MAS compounds are all compounds of the general formula I, la, lb, and Jc mentioned
`in any of the international patent applications having the international publication number WO
`96/00235 (our.ref.: 4228), WO 97/00864 (our ref.: 4475), WO 98/28323 (our ref.: 5141), WO
`99/32506 (earliest priority: 971218), WO 98/52965 (earliest priority: 970516), WO 99/67273
`(our ref.: 5558), WO 99158549 (our ref.: 5509), or WO 2000/47604 (our ref.: 5769), WO
`25 · 2000/68245 (our ref.: 6238), or WO 2001/62771 (our ref.: 6239), preferably all the specific
`
`compounds mentioned specifically in said WO specifications covered by said formula, as well
`as compounds of the general formula X shown below:
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`R20
`
`4
`
`)
`R
`
`-R23'
`
`wherein in the moiety of the following formula
`
`x.
`
`,
`
`XA
`each bond between c5 and C6, between C6 and C7, between C7 and C8
`, between c8 and C9
`between cs· and C14 and between C 14 and C16
`, independ~ntly, is a single bond or a double
`bond, at least one of these bOnds being a double bond, and wherein each carbon atom C5
`,
`, C1
`C 6
`, C14 and C16 is bonded to each neighbouring C. atom by a single bond or at the
`, C8
`, C9
`most by one double bond, and Wherein between all other carbon atoms of the steroid skele-
`. ton are single bonds, and C3R3 ls a) c3=0 orb) C3H-OR3', wherein R3
`' is selected from the
`group, comprising hydrogen, unsubstituted or substituted, linear or branched c, - C10 alkyl
`·, bonded to the CH~O moiety via the C(O) moiety, where~n R3" is selected from
`and C3(0)-R3
`the group, comprising i) substituted or unsubstitu~ed, linear or branched C1 - C10 alkyl, ii)
`substituted or unsubstituted, linear or branched C1 - C10 fluoro alkyl, iii) unsubstituted or sub(cid:173)
`stituted C8 - C10 aryl, iv) unsubstituted or substituted Cs - C1o heteroaryl, v) unsubstituted or
`substituted, linear or branched C1 - C10 alkyloxy and vi) unsubstituted or substituted, linear or
`• or c3=NOR3", wherein R3
`branched C1 - C10 alkylamino, or c) C3H-S0z-R3
`• has the same
`meaning as above, or d) c3H-0-R3
`-, wherein R3
`"' Is unsubstituted or substituted, linear or
`branched C2 - C10 alkylen and forms a cyclic ether both with the C atom of the steroid skele(cid:173)
`ton and the O atom, ore) a cyclic ring structure with the C3 atom, wherein R3 is unsubstituted
`or substituted, linear or branched C2 - C 10 alkylen, or f) c3H-Hal, wherein Hal is F, Cl, Br oi-1,
`
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`5
`' and R2°, independently, are selected from the group, comprising hydrogen and
`and R4. R4
`unsubstituted or substituted, linear or branched C1 - C4 alkyl, and R23 and R23', independently,
`are selected from the group, comprising: a) hydrogen, b) unsubstituted or substituted, linear
`or branched ~ - C8 alkyl, c) unsubstituted or substituted, linear or branched C2 ~ Ca alkenyl,
`d) unsubstituted or substituted, linear or branched C1 - Ce alkyl, at least one of tne alkyl car.;.
`bon atoms being substituted by any of 0, N.and s. e) unsubstituted or substituted; linear or_
`branched~ -C8 alkenyl, at least one.of the alkenyl carbon atoms being substituted by any
`of 0, N and S and f) unsubstituted or substituted, linear or branched Ce. - C10 aryl, or R23 and
`· . ·R23' together form a) an unsubstituted or substituted, linear or branched C2 - Cr alkylen, es-
`pecially C5 - Cr. group orb) an unsubstituted or substituted, linear or branched~ - C1 al-
`. kylen, especially Cs - Cr. group, whe.rein at lee1st one of the alkylen carbon atoms Is rep_laeed
`..
`by any of 0, N ~nd S, and A is a methylen or ethylen group, the group being unsubstituted or
`substituted methylen or ethylen; hi a preferred embodiment of the present invention A is me(cid:173)
`thylen or ethylen .
`
`The content of the above WO specifications is hereby incorporated by reference.
`
`Preferred compounds of formula X·are such in which at least one double bond is present in
`, C°, c9, C14 and C15
`the steroid skeleton between ~rbon atoms C°, C7
`, respectively. In one
`further:.preferred embodi~ent of this invention, a double bond may be prese~t betWeen C5
`, C14 and C15
`und C8 In addition to the at least one double bond ~tween C6
`, ~
`, C7
`, C8
`, C9
`spectively. It is especially preferre:d to have a steroid in which the double bonds are conju(cid:173)
`gated to each other if more than one double bond Is present in the steroid skeleton.
`
`All Indications to Cn alkyl; Cn fluoroalkyl, Cn alkyloxy, Cn alkylamino, C~ cycloalkyl, Cn
`alkylen, Cn alkenyl, Cn aryl, Cn heteroaryl and the like rela~e to radicals with n carbon atoms
`in the moiety t the number Of n carbon atoms including all carbon atoms in side chains of for .
`
`example, branched radieals. Unless otherwise described herein, an alkyl, alkoXy, alkylen or
`acyl group has 1 to 10 carbon atoms including side chain .carbon atoms if these groups are
`branched; an alkenyl or alkynyl group has 2 to 1 O carbon atoms including side chain carbon
`atoms if these groups are branched; further a cycloalkyl has 4 to 7 carbon atoms; an aryl has
`6 to 1 O carbon atoms; and a heterocyclic ring or a heteroaryl have 6 to 1 O ring atoms. Further
`
`aryl also represents alkylaryl; heteroaryl also represents alkylheteroaryl; and cycloalkyl also
`represents alkylcycloalkyl.
`
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`6
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`The novel steroid compounds of formula X have a number of chiral centers such
`that these compounds exist in several isomeric fonTlS. All these isomeric forms are Within the
`
`scope of the present invention unless otherwise described herein.
`
`5
`
`A steroid compound with the general formula below.is preferred:
`
`A
`'-.. ·--R23'
`
`f
`
`.
`
`R23
`
`CH3
`
`c14_
`,, "'·
`
`~c1s
`
`ltcg
`'rB ..
`
`I
`I
`I
`
`~c)(~s,, ~.c1
`~ cs
`R3
`H'
`R4'
`
`R4
`
`,
`
`.
`
`.
`
`10
`
`14-pregnadien derivatives, the a8-pregnene
`Especially the ll.5-pregenene derivatives, the ll.8
`•
`5
`7-pregnadiene derivatives are useful as pharmaceutically active steroid
`derivatives and the f).
`•
`compounds, i.e. compounds having the general formulae shown below:
`
`XB'
`
`XB"
`
`XB""
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`
`Th~ outstanding properties of the novel compounds may be attributed to the amino group in
`the .side chain linked to the C17 carbon atom in the steroid skeleton via a Ca - ~.alkylen
`spacer (including the c2°-R20 group).
`Especially preferred are compounds, wherein the moiety C3R3 is CH-OH, in particu-
`lar a 3~hydroxy radical bonded to the c3 atom of the steroid skeleton. The moiety may also
`be CH-0-C(O)-R3'0 (= CH-O-R3
`
`', wherein R3' is C(O)-R3''), wherein R3" is defined as before. In
`·particular R3 may be an ester radical of a rnonocarboxyllc acid, of a dicarboxylic, acid, of an
`inorganic acid or of any other ac!d, bonded to the C3 atom of the steroid skeleton. Especially
`for R3 being an ester radica.1 ofa dicarb~xyllc acid R3" may be (CH2)n-COOH, wherein n = 1~
`2, 3, 4, 5 or 6. The ester radical rriay also be formed from an Inorganic acid such as phos-.
`
`phoric acid, sulfuric acid and sulphamic acid, further· from a monocarboxylic acid such as
`
`acetic acid, proplonic acid, n-butanoic acid, plvalic acid, benzoic acid, nicotinic acid and
`
`isonicotinic acid. In particular the ester rad.ieal may be formed from a d!carboxylic acid, suCh
`
`as from succinic acid and glutaric acid.
`.Further steroid compounds. according to the present invention may also include de-
`rivative.s, In which C-O-R3 represents a·cyclic ether including the C3 atom 9f the steroid skele- ·
`ton.
`
`· R3 may also form a cyclic ring structure together with the c3 atom, R3 being unsub- ·
`stltuted or substitute.d, iinear or branched Ca - C10 alkylen. For example, c3R3 may .be a
`cyclopropylen, cyclobutylen, cyclopentyfen or cyclohexylen radical. It may also represent an
`
`unsaturated cyclic ring structure such as cyclopropenylen, cyclobutenylen, cyclopentenylen
`
`and cyclohexenylen.· The ring structure may also be substjtuted by any of halogen, hydroxy,
`alkoxy, aryloxy and the like.
`Substa.nces according to the present invention may advantangeously ~Isa be com-
`pounds, in which R3" is selected from the group comprising fluoromethyl, aryl, heteroaryl and
`(CH2)n-COOH, wherein n = 1, 2, 3, 4, 5 or 6, especially compounds, in which R30 (= C(O)-R3
`is acetyl; propionyl, pivaloyl,butanoyl, benzoyl, nicotinyl, isonlcotinyl, heml glutaroyl, butyl(cid:173)
`
`carbamoyl, phenylcarbamoYt, ethoxycarbonyl and terl-butoxyearbonyl. 'in a particularly pre(cid:173)
`ferred steroid compound RS' may be hemi succlnoyl.
`Further in the novel steroid compounds R4 and R4
`', independently, are preferably
`hydrogen or a linear or branched C1 - C4 alkyl group, i.e. methyl, ethyl, propyl and butyl, and
`especially methyl.
`Further R4 and R4
`', independently, may also be C1 - C4 alkyl, substituted by halogen,
`hydroxy, alkoxy or aryloxy.
`
`.)
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`8
`R20 is preferably hydrogen or linear or branched Ci - C4 alkyl, i.e. methyl, ethyl, pro(cid:173)
`pyl and butyl. R20 is especially methyl.
`R23 and R23', independently, may specifically be hydrogen or a C1 - Cs alkyl group,
`such as methyl, ethyl, n-propyl, /so-propyl, n-butyl, iso-butyl, terl-butyl, .n-pentyl, iso-pentyt,
`terl-pentyl, neo-pentyl, further hexyl and cydohexyland the like. Further R23 and R23', ind&(cid:173)
`pendently, may also be a C? - C8 alkenyl group, i_.e. an unsaturated alkyl group, for example,
`vinyl, allyl, isa:-propenyi ~nd prenyl, furtner Ce·- C10 aryl, such as phenyl and 1-naphthyl, this
`group also comprising alkylaryl, being bonded via the aryl moiety or via the alky.1 moiety to
`the nitrogen atom, for example, beniyl and tolyl. R23 and R23' may preferably be alkyl and
`alkenyt,· being substituted by at least one radical, selected from the group, comprising linear
`or branched c, - C4 alkyl and C1 - C4 alkoxy. The. phenyl and 1-naphthyl radical· may also be
`substituted by halogen, C1 - C4 alkoxy, hydroxy or C1 - C4 alkyl, including the fluoroalkoxy
`and fluoro~lkyl derivatives. Further R23 and R23', independently, may further be for example,
`4-hydroxyphenyl, 4-methoxyphenyl, 2,4,6-trimethylphenyl, 2,4-dichlorophenyl, 4-
`
`fluorophenyl, 4-trifluoromethylphenyl and 2-pentafluoroethylphenyl.
`Further R23 and R~. independently, may ~lso represent alkyl and alkenyl, at least
`o_ne of the alkyl and alkenyl carbon atoms, respectively, being replaced by any of 0, N and S,
`for example, methoxymethylen, methoxyethylen, methoxypropylen, ethoxypropylen and the
`
`5
`
`1 O
`
`15
`
`like.
`
`20
`
`R23 and R23' together may also form a heterocyciic ring structure bonded to the side
`chain via the nitrogen atom in the side chain, the nitrogen atom being linked to the C20 car- .
`
`bo~ atom of the steroid skeleton via the spacer group A. This heterocyclic ring structure,
`formed by N(R23)(R23'), .may especially be a moiety being selected from the gro~p, comprising
`piperidin-1-yl, morpholin+.yl, piperazin-1-yl; pyrrolidin-1-yl, pyrrol-1-yl, indol-1-yl, pyrazol-1-
`
`25
`
`yl, imidazol-1-yl, thiazolidin,-1-yl and oxazolidin-3-yl ring structures and substituted derivatives
`
`thereof. Especially preferred heterocyclic ring structures are the saturated· radieals, namely
`
`piperidin-1-yl, morpholin-4-yl, piperazin-1-yl and pyrrolidln-1-yl. The heterocycilc ring struc-
`
`. tures may be substituted with hydroxY, carboxy, amino, alkylamino, dialkylamino, alkyl, al(cid:173)
`
`kenyl, alkynyl, cycloalkyl, cycloalkenyl, alkylcycloalkyl, aryl, alkylaryl, hydroxy, alkoxy, alkyl-
`cycloalkyloxy, alkyloxycycloalkyl, alkylaryloxy, alkyloxyaryl, halogen and acyl, wherein alkyl,
`
`30
`
`alkenyl, alkynyl, cycloalkyl, aryl, alkoxy and acyl have a number of carbon atoms as indicated
`
`above. The heterocyciic ring structure may also be substituted with heterocyclic radicals,
`
`su_ch as the heterocycllc ring structures to which they may be bonded and in addition.to these
`
`as the further radicals, for example, pyridinyl, chinollnyl, isochinolinyl, pyridazinyl, pyrimidinyl,
`pyrazinyl, chinoxalinyl, thiazolyl and oxazolyl, further including all other isomers of these
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`radicals, for example, pyridin-2-yl, 'pyridin-3-yl and pyridln-4-yl. Further if N(R23)(R23') is a het- _ ·
`erocyclic ring structure this ring structure may also include an oxo group in the ring.
`
`9
`
`5
`
`If N(R23)(R23) is piperazin-1-yl this moiety may be especially substituted by pyridln-2-
`yl, pyridin-3-yl and pyridin-4-yl, to preferably give the respective N(R23)(R23') groups in which
`the piperazin-1-yl group. is substituted in para-position, for example, 4-(pyridin-3-yl)piperazin-
`
`1-yl.
`
`
`
`N(R23)(R23) may also be any moiety shown of the following formula:
`
`0
`
`.10
`
`bonded to c2° in the side chain of the steroid skeleton via the nitrogen atom of this moiety,
`wherein Z = 0, S, N-R24
`, wherein R24 is alkyl, alkenyl, alkynyl, aryl, the number
`, N-C(O)-R24
`of carbon atoms of which Is defined as above. Further R24 may be a heterocyclic ring struc(cid:173)
`ture, wherein the number of ring atoms is as defined above.
`The nitrogen atom.of N(R23)(R23') is not bonded directly but via A to the c?SJ atom;
`15 wherein A is an unsubstituted or substitl.ited methylen or ethylen spacer group, such as for
`
`example, {unsubstlt1.,1ted) methylen and (unsubstituted) ethylen and further iso-propylen, tert(cid:173)
`bl!tylen and the like~ Preferably A. ls methylen and ethylen.
`Especially preferable are compounds, in which R3 is hydroxy or hemi su~nate es- ·
`' and R2D are each methyl and in which the heterocyclic ring structure
`· .ter, in which R4
`, R4
`20 N(R23)R23
`) Including the amino ni~rogeil atom is an unsubstituted or substituted:morpholln-4-
`yl, piperidin-1-yl, piperazin-1- or pyrrolidin-1-yl. N(R23)(R23
`) Is In particular 3-hydroxypiperidin-
`1 ~yl, 4-hydroxy-piperidin-1-yl, 3-ketopiperidin-1-yl, 4-ketopiperidin-1-yl, ·4-dimethytamino(cid:173)
`pipendin-1-yl, 3,3-dimethylpiperidin-1-yl, 4,4-dimethylpiperidin-1-yl, 3-carboxypiperidin-1-yl,
`
`4-tarboxy-piperidin, 4-phenylpiperidin-1-yl; 4-benzoyl-piperidln-1-yl, 4-(piperidin-1-yl)-
`
`25
`
`piperidin.;.1-yl, 4-methylpiperazin-1-yl, 4-acetylpiperazin-1-yl, 4-phenylplperazin-1-yl, 4-
`
`berizylpiperazin-1-yl, 4-benzoylpiperazln-1-yl, 4-(pyrldin-2-yl)plperazin-1-yl, 4-(pyridin-4-yl)(cid:173)
`
`.piperazin-1-yl, 4-{pyrtmidin-2-yl)piperazin-1-yl.
`Hydrogen atoms may be bonded to all other skeleton C atoms of the steroid corri(cid:173)
`pounds, I.e. to C1
`, C2
`, C6
`, C7
`, C8
`, C9
`, C11
`, C12
`
`, C14, C15 and C16
`•
`. Preferably pharmaceutically acceptable compounds of the present invention are
`salts of steroid compounds of general formula X. Examples of these salts are listed in Jour(cid:173)
`nal of Phannaceutical Science, 66, 2 et seq. (19n), which are hereby incorporated by refer(cid:173)
`ence. Examples of such salts Include salts of organic acids such as formic acid, fumaric acid,
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`
`10
`
`acetic acid, proplonic acl~. glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid,
`
`malic acid, tartaric acid, cibic acid, benzoic acid, salicylic acid, methane sulphonic acid and
`
`the like. Suitable inorganic acids to form pharmaceutically acceptable salts include hydro(cid:173)
`
`5
`
`chloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like.
`The use of the following compounds according to the present invention is especially
`preferred:
`
`10
`
`15
`
`20
`
`1)
`
`2)
`
`3)
`
`4)
`
`5)
`6)
`7)
`
`8)
`9)
`
`{2?5)-20-[(3,3-dimethylpiperidin-1-yl)methyl]-4,4-dimethyl-5a-pregna-8, 14-dien-313-ol; ·
`
`· (205)-20-[(plperidin-1-yl)methyij-4,4-dimethyl-~-pregna-8, 14-dien-313-ol;
`
`(20S)-20-[(4,4-dimethylpiperidln-1-yf)methyl]-4,4-dimethyl-5a:-pregna-8, 14-dien-3JH>I; ·
`
`(205)-20-[( 4-methylplperazin-1-yl)methyl]-4,4-dimethyl-Sa-pregna-8, 14-dien-313-ol;
`(205)-20-[( 4-phenylpiperazin-1-yl)methyij-4,4-dimethyl-5a-pregna-8, 14-dlen-313-ol;
`
`(20S)-20-[(morpholin-4-yl)methyij-4,4-dimethyl-5a-pregna-8, 14-dlen-3j3-ol;
`(205)-20-[(4-(pyrimldln-2-yl)piperazin-1-yl)methyij-4,4-dlmethyl-5a-pregna-8, 14-dien-313-
`ol;
`
`(20S)-20-[(pyri'olidin-1-yl)methyij-4,4-dimethyl-5a-pregna-8, 14-dien-313-ol;
`· (20S)-20-[(3,3-dimethylpiperidin-1-yl)methy1J-4,4-dimethyl-5a-pregna-8, 14-dien-3~1
`hemisuccinate;
`
`10) (20S)-20-[N-(3-methoxypropyl)aminomethyij-4,4-dimethyl-5a-pregna-8,14-dien-313-ol;
`
`11) (20S)-20-aminomethyl-4,4-dimethyl-5a-pregna-8, 14-dien-313-ol;
`12) (205)-20-[N,N-di-(2-methoxyethyl)aminomethyl}-4,4-dlmethyl-5a-pregna-8, 14-dien"'.313-ol;
`13) (205)-20-(N-(2,2-dlmethylethylen )aminomethyij-4,4-dimethyl-5a-pregna-8,.14-dien-3j3-ol;
`14 ). (205)-20-[(piperidin-1-yl)methyl]-4,~lmethyl-5a-pregna-5, 7-dien-313-DI;
`
`15) (205)-20-[( 4-(pyridin-2-:Yl)piperazin-1-yf)ethyij-4,4-dimethyl-Sa-pregna-8, 14-dien-313-ol;
`25 . 16) (205)-20-(( 4-phenylplperazin-1-yl)ethyij-4,4-dimethyl-5a-pregna-8, 14-dien-3P-ol;
`
`17) (205)-20-[(4-methylpiperazin-1-yl)ethyl]-4,4-:dimethyl-5a-pregna-8, 14-dien-3p-ol; ·
`
`30
`
`18) (205)-20-[(N,N-dlmethylamino)ethyl]-4,4-dlr'nethyl-5a-pregna-8, 14-dlen-3~1;
`19) (205)-20-[(morpholin-4-yl)ethyij-4,4-dimethyl-5a-pregna-8, ~ 4-dlen-3~1;
`.
`20) (205)-20-[{pyrrolidin-1-yl)ethyl]-4,4-dimethyl-5a-pregna-B, 14-dien-313-ol;
`21) (205)-20-[(piperidin-1-yl)ethyij-4,4-dimethy1-5a-pregna-8, 14-dien-3J3-ol;
`22) {205)-20-[( 4-phenylpiperldin-1-yl)methyij-Sa-pregna-5-en-313-ol;
`23) (20S)-20-[(piperidln-1-yl)methyll-5a-pregna-5-en-3j3-ol;
`24) (20S)-20-[(morpholin-4-yl)methyl]-5a-pregna-5-en-3j3-ol;
`
`.
`
`25) (205)-20-[(pyrrolidin-1-yl)methyij-5a-pregna-5-en-3~-ol;
`26) (20S)-20-[(4-carboxyethylpiperidin-1-yl)methyl]-5a-pregna-5-en-3~1;
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`35
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`11
`
`27) (208)-20-[(3-hydroxypiperidln-1-yl)methyl]-5a-pregna-5-en-3J3-ol;
`
`28) (208)-20-[( 4-benzoylpiperidin-1-yl)methyij-5a-pregna-5-en-3(3-ol;
`
`29) (208)-20-[( 4-(piperidin-1-yl)piperidin-1-yl)methyl]-5a-pregna-5-en-3f3-ol; ·
`
`30) (208)-20-[( 4-thiomorpholinyl)methyl]-5a-pregna-5-en-3(3-ol;
`
`5
`
`31) (208)-20-[( 4-dimethylaminopiperidin-1-yl)methyij-5a-pregna-5-en-3(3-ol;
`
`32) (208)-20-[( 4-ketopiperidin-1-yl)methyl]-5a-pregna-5-en-3f3-ol;
`
`33) (208)-20-[(3-ketopiperidin-1-yl)methyij-5a-pregna-5-en-3f3-ol;
`
`34) (208)-20-[( 4-carboxylpiperidin-1-yl)methy1J-5a-pregna-5-en-3(3-ol;
`
`35) (208)-20-[(3-carboxylpiperidin-1-yl)methyl]-5a-pregna-5-en-3J3-ol;
`
`1 O
`
`36) (208)-20-[( 4-hydroxypiperidin-1-yl)methy1J-5a-pregna-5-en-3(3-ol;
`
`37) {208)-20-[(3,3~dimethylpiperidin-1-yl)methy1J-5a-pregna-5-en-3(3-ol;
`
`38) (208)-20-[( 4,4-dimethylpiperidin-1-yl)methyij-5a-pregna-5a-en-3(3-ol;
`
`39) (208)-20-[(4-piperazin-1-yl)methyl]-5a-pregna-5-en-3J3-ol;
`
`40) (208)-20-[( 4-phenylpiperazin-1-yl)methy1J-5a-pregna-5-en-3J3-ol;
`
`15
`
`41) (208)-20-[(4-methylpiperazin-1-yl)methyij-5a-pregna-5-en-3J3-ol;
`
`42) (208)-20-[(4-benzylpiperazin-1-yl)methyij-5a-pregna-5-en-3J3-ol;
`
`43) (208)-20-[(4-acetylpiperazin-1-yl)methyij-5a-pregna-5-en-3J3-ol;
`44} (208)-20-[(4-benzoylplperazi.n-1-yl)methyl]-5a-pregna-5-en-3J3-ol;
`45) (208)-20-[{4-(2-pyridyl}piperazin-1-yl}methyij-5a-pregna-5-en-3(3-ol;
`
`20
`
`46) (208)-20-[{4-(3-pyridyl)piperazin-1-yl}methyij-5a-pregna-5-en-3j3-ol;
`
`47) (208)-20-[{4-(4-pyridyl)piperazin-1-yl}methyij-5a-pregna-5-en-3j3-ol;
`48) (208)-20-[{4-(2-pyrimidyl)piperazln-1-yl}methyij-5a-pregna:-S-en-3J3-ol;
`49) (208)-20-[(piperidin-1-yl)methylJ-4,4-dimethyl-5a-pregna-A 5<14>-en-3J3-ol;
`
`50) (208)-20-[(piperidin-1-yl)methyij-4,4-dimethyl-5a-pregna-5-en-3J3-ol;
`
`25
`
`51) (20S)-20-[(morpholin-4-yl)methyl]-4,4-dimethyl-5a-pregna-5-en-3J3-ol;
`
`. 52) (208)-20-[(thiomorpholin-4-yl)methyij-4,4-dimethyl-5a-pregna-5-en-3J3-ol;
`
`53) (20S)-20-[(4-methylpiperidin-1-yl)methyl]-4,4-dimethyl-5a-pregna-5-en-3J3-ol;
`
`54) (208 )-20-[(3-methylpiperidin-1-yl)methy1J-4,4-dimethyl-5a-pregna-5-en-3J3-ol;
`
`55) (20S}-20-[(4-(pyrimidin-2-yl)piperazin-1-yl)methyij-4,4-dlmethyl-5a-pregna-5-en-3J3-ol;
`
`30
`
`56) (20S).:.20-[(4-hydroxypiperidin-1-yl)methylJ-4,4-dimethyl-5a-pregna-5-en-3J3-o1;
`
`57) (208)-20-[(3-hydroxymethylpiperidin-1-yl)methyg-4,4-dlmethyl-5a-pregna-5-en-3J3-ol;
`
`58) (20S)-20-[(4-methylplperazin-1-yl)methyij-5a-pregna-8, 14-dlen-313-ol;
`59) (20S )-20-[(3-methylpiperidln-1-yl)methyg-sa-pregna-A 5<14>-en-3(3-ol;
`60) (20S}-20-[(3-pyrrolin-1-yl)methy1J-4,4-dimethyl-5a-pregna-8, 14-dien-3J3-ol;
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`12 of 34
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`
`61) {20S)-20-[{thiomorpholin-4-yl)methyQ-4,4-dimethyl-5a-pregna-8, 14-dien-3[3-ol; and
`
`62) 4,4-dimethyl-5a-cholesta-8, 14,24-triene-3J3-ol.
`
`12
`
`The structural formulae of compounds nos. 1-49 are shown in Fig. 1A- Fig. 1K in WO
`
`5
`
`02/079220 which was published after the priority date of this application.
`
`A further object of the present invention is pharmaceutical compositions comprising
`
`at least one MAS compound and at least one pharmaceutically acceptable excipient well
`known in the art, for example, at least one carrier, diluent, absorption enhancer, preservative,
`buffer, agent for adjusting the osmotic pressure and rheology of the medicament if it will be
`
`1 O
`
`liquid, surfactant, solvent, tablet disintegrating agent, micro capsules, fHler, slip additive, col(cid:173)
`orant, flavour and other Ingredient. These substances are conventionally used in the art. The
`steroid compounds used according to the present invention (i.e. the MAS compounds) are
`
`. 15
`
`20
`
`25
`
`. preferably comprised in the pharmaceutical compositions in an effective amounl
`. Examples for solid carriers are magnesium carbonate, magnesium stearate, dextrin,
`lactose, sugar, ~lkum, gelatin, pectin, starch, silica gel, tragacanth, methylcellulose, sodium
`carboxymethyl cellulose, low melting waxes and cacao butter.·
`Liquid compositions include sterile solutions, suspensions and emulsions, which
`may· be. administered for. e~mple, orally by nasal administration or as an ointment. Such liq-
`uid oompositions may also be suitable for injection or for use in connection with ex vjVo or in
`vivo application. For oral administration the liquid may contain a pharmaceutically acceptable
`oil and/or lipophilic, surfactant and/or solvent which is miscible with water. In this connection
`.reference is made to WO 97/21440 A1, which is hereby incorporated by reference~
`· · Liquid compositions may also contain other ingredients, which are conventionally
`used in the art, some of which are mentioned in the list above. Further.a composition for·
`.
`transdermal administration of a compound of the present invention may be provJded in the
`form of a patch. A composition for nasal administration may be provided In the form of a na(cid:173)
`sal spray in liquid or In powder form.
`
`'
`
`'
`
`