111111111111111111111111111111111111111111111111111111111111111111111111111
`US0073171 09B2
`
`c12) United States Patent
`Campbell et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,317,109 B2
`*Jan.8,2008
`
`(54) PYRROLIDINE COMPOUNDS AND
`METHODS FOR SELECTIVE INHIBITION
`OF DIPEPTIDYL PEPTIDASE-IV
`
`(75)
`
`Inventors: David Alan Campbell, San Diego, CA
`(US); David T. Winn, San Diego, CA
`(US); Juan Manuel Betancort, San
`Diego, CA (US)
`
`(73) Assignee: Phenomix Corporation, San Diego,
`CA (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`(21) Appl. No.: 111381,085
`
`(22) Filed:
`
`May 1, 2006
`
`(65)
`
`Prior Publication Data
`
`US 2006/0264400 Al
`
`Nov. 23, 2006
`
`Related U.S. Application Data
`
`(63) Continuation-in-part of application No. 10/514,575,
`filed on Oct. 27, 2005.
`
`(60) Provisional application No. 60/519,566, filed on Nov.
`12, 2003, provisional application No. 60/557,011,
`filed on Mar. 25, 2004, provisional application No.
`60/592,972, filed on Jul. 30, 2004, provisional appli(cid:173)
`cation No. 60/676,808, filed on May 2, 2005.
`
`(51)
`
`Int. Cl.
`A61K 31169
`(2006.01)
`C07F 5102
`(2006.01)
`(52) U.S. Cl. ......................................... 548/405; 514/64
`(58) Field of Classification Search ................. 548/405
`See application file for complete search history.
`
`5,385,929 A
`5,447,954 A
`5,462,928 A
`5,488,064 A
`5,491,134 A
`5,541,204 A
`5,574,017 A
`5,594,016 A
`5,595,872 A
`5,614,492 A
`5,631,224 A
`5,686,104 A
`5,712,279 A
`5,712,396 A
`5,739,135 A
`5,760,246 A
`5,770,615 A
`5,776,983 A
`5,827,875 A
`5,885,983 A
`5,952,301 A
`5,952,322 A
`5,962,440 A
`5,965,532 A
`
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`(Continued)
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`FOREIGN PATENT DOCUMENTS
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`U.S. PATENT DOCUMENTS
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`
`Primary Examiner-Laura L. Stockton
`(74) Attorney, Agent, or Firm-Schwegman, Lundberg &
`Woessner P.A.
`
`(57)
`
`ABSTRACT
`
`The present invention is directed to pyrrolidinylaminoacetyl
`pyrrolidine boronic acid compounds that display selective,
`potent dipeptidyl peptidase IV inhibitory activity. These
`compounds are useful for the treatment of disorders that can
`be regulated or normalized via inhibition ofDPP-IV includ(cid:173)
`ing those characterized by impaired glycemic control such
`as Diabetes Mellitus and related conditions. The compounds
`can be administered alone or with another medicament that
`displays pharmacological activity for treatment of these and
`other diseases.
`
`27 Claims, No Drawings
`
`Boehringer Ex. 2013
`Mylan v. Boehringer Ingelheim
`IPR2016-01566
`Page 1
`
`

`
`US 7,317,109 B2
`Page 2
`
`U.S. PATENT DOCUMENTS
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`Boehringer Ex. 2013
`Mylan v. Boehringer Ingelheim
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`
`US 7,317,109 B2
`
`1
`PYRROLIDINE COMPOUNDS AND
`METHODS FOR SELECTIVE INHIBITION
`OF DIPEPTIDYL PEPTIDASE-IV
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`2
`cal cycles. Thus, the difficulty concerning inhibitors of
`DPP-IV is that they can also affect the other members of the
`enzyme group. The evidence indicates that, for example,
`other inhibitors of DPP-IV, which also inhibit the other
`5 amino-dipeptidases such as DPP-VIII, will cause toxic
`effects in animals.
`Accordingly, a need exists for compounds that are useful
`for inhibiting DPP-IV without an adverse event profile that
`precludes chronic administration.
`
`SUMMARY OF THE INVENTION
`
`This application is a continuation-in-part of U.S. appli(cid:173)
`cation Ser. No. 10/514,575, filed on Oct. 27, 2005, which is
`a national stage application of PCTIUS04/037820, which 10
`claims priority to U.S. provisional application No. 60/519,
`566, filed on Nov. 12, 2003; U.S. provisional application No.
`60/557,011, filed on Mar. 25, 2004; and U.S. provisional
`application No. 60/592,972, filed on Jul. 30, 2004. This
`application is also a continuation-in-part of U.S. application 15
`Ser. No. 60/676,808, filed on May 2, 2005. These applica(cid:173)
`tions are incorporated herein by reference.
`
`The present invention is directed to a selective DPP-IV
`inhibitor and methods of use that are effective in treating
`conditions that may be regulated or normalized by inhibition
`of DPP-IV. More particularly, the invention is directed to a
`pyrrolidinylaminoacetyl pyrrolidine boronic acid com(cid:173)
`pound. This pyrrolidinylaminoacetyl pyrrolidine boronic
`acid compound is useful at effective doses for treatment of
`20 malconditions associated with DPP-IV activity and is a
`selective inhibitor of DPP-IV.
`A pyrrolidinylaminoacetyl boronic acid compound of the
`invention (hereinafter the pyrrolidine compound of the
`invention) has a structure represented in part by Formula I.
`
`FIELD OF THE INVENTION
`
`The present invention relates to a pyrrolidinylaminoacetyl
`pyrrolidine boronic acid compound and its use as a selective
`inhibitor of post-proline/alanine cleaving amino-dipepti(cid:173)
`dases, particularly dipeptidyl peptidase-IV (DPP-IV). The
`invention also relates to methodology for employing a 25
`pyrrolidine compound, alone or with another medicament, to
`treat a DPP-IV-related disease, including but not limited to
`disorders characterized by impaired glycemic control, espe(cid:173)
`cially Diabetes Mellitus and related conditions. Thus, the
`invention has applications in the medicinal, chemical, phar- 30
`macological, and medical fields.
`
`BACKGROUND OF THE INVENTION
`
`(I)
`
`Dipeptidyl peptidase-IV (DPP-IV) is a serine protease 35
`that belongs to a group of post-proline/alanine cleaving
`amino-dipeptidases. DPP-IV catalyzes the release of an
`N-terminal dipeptide of any configuration from proteins, and
`preferably, the dipeptide contains anN-terminal penultimate
`proline or alanine.
`The physiological role of DPP-IV has not been estab(cid:173)
`lished fully. It is believed to play an important role in
`regulatory peptide metabolism, which, among other things,
`controls various physiological functions including but not
`limited to glycemic control and insulin sensitivity. In par- 45
`ticular, DPP-IV has been implicated in the control of glucose
`metabolism because its substrates include the insulinotropic
`hormones, glucagon like peptide-! (GLP-1) and gastric
`inhibitory peptide (GIP), which are inactivated by removal
`of their two N-terminal amino acids.
`In vivo administration of synthetic inhibitors of DPP-IV
`prevents N -terminal degradation of insulinotropic hormones
`including, GLP-1 and GIP, resulting in higher plasma con(cid:173)
`centrations of these hormones, increased insulin secretion
`and, consequent improved glucose tolerance. Therefore, 55
`such inhibitors have been proposed for the treatment of
`patients with impaired glycemic control such as Diabetes
`Mellitus and related conditions.
`This proposal has significant difficulties, however. Addi(cid:173)
`tional dipeptide cleaving amino-dipeptidases have also been 60
`discovered, including DPP-VII, DPP-VIII, DPP-IX, and
`fibroblast activation protein (FAP), which can have substrate
`and inhibitor specificity similar to DPP-IV. The precise
`physiological role of each of these dipeptide cleaving
`enzymes is not well defined. But, their propensity to cleave 65
`N-terminus dipeptides from proteins in general indicates that
`these amino-dipeptidases are involved in many physiologi-
`
`The substituents and bond designations of formula I
`include R2 and R3
`, which, independently or together, are
`---OH, -O-M+ wherein M+ is a cation, a hydroxyl bearing
`a boronic acid protecting group, or a group capable of being
`hydrolyzed to a hydroxyl group in an aqueous solution at
`40 physiological pH or in biological fluids; and the wavy lines
`at asymmetric carbons ca and C6
`, which independently
`indicate for each asymmetric carbon an R configuration, an
`S configuration, or a mixture of both configurations such that
`all stereoisomers and all stereomeric mixtures are included.
`Also included within the scope of the invention are a cyclic
`isomer
`thereof, any pharmaceutically acceptable salt
`thereof, any prodrug thereof, and any solvate thereof.
`A pyrrolidine compound of the invention may exist in
`either of two forms, the linear form represented by formula
`50 I above and the cyclic isomer form represented by formula
`V below.
`
`(V)
`
`The cyclic isomer form and the linear form are in thermo(cid:173)
`dynamic equilibrium when in solution. The equilibrium
`
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`
`US 7,317,109 B2
`
`3
`shifts depending upon pH. Thus, the predominance of one
`form over the other in solution depends upon the pH so that
`at acidic pH, the linear isomer predominates while at basic
`pH, the cyclic isomer predominates. The linear and cyclic
`isomers are also stable such that either form may be isolated 5
`as a solid. The isolated cyclic isomer can function as a
`prodrug.
`The invention also is directed to a pharmaceutical com(cid:173)
`position containing a pyrrolidine compound of the invention
`and a pharmaceutical carrier. The pharmaceutical composi(cid:173)
`tion may be formulated to be dosed by any administrative
`route including but not limited to parenteral injection, oral,
`buccal, rectal and the like.
`The invention is as well directed to a method of treatment
`of a malcondition that can be regulated or normalized via 15
`inhibition ofDPP-IV. The method involves administration of
`an effective amount of a pyrrolidine compound of the
`invention, such as would be present in a pharmaceutical
`composition of the invention, to mmals, especially
`humans, to affect a malcondition that can be regulated or
`normalized via inhibition ofDPP-IV. Preferably, an effective
`amount of a pyrrolidine compound of the invention exhibits
`lower toxicity than do non-selective inhibitors of DPP-IV,
`particularly in comparison to boronic acid inhibitors of
`DPP-IV that also display inhibition of other DPP enzymes
`and FAP. Therefore, the invention is directed to methods for
`selectively inhibiting DPP-IV including administering to a
`patient in need of such treatment a therapeutically effective
`amount of a pyrrolidine compound of the invention.
`The invention further is directed to a pharmaceutical
`combination of a pyrrolidine compound of the invention and
`one or more other medicaments that are useful for treatment
`of a malcondition that can be regulated or normalized via
`inhibition of DPP-IV. Such malconditions are associated
`with impairments in glycemic control especially Diabetes
`Mellitus and related conditions. A pharmaceutical combina(cid:173)
`tion may be formulated according to the invention as a
`pharmaceutical composition.
`The invention is also directed to a process for preparing
`a pyrrolidine compound of the invention, a method for 40
`preparing a pharmaceutical composition of the invention,
`and the use of a pyrrolidine compound of the invention in a
`method for the preparation of a medicament for treating a
`malcondition that can be regulated or normalized via inhi-
`bition of DPP-IV.
`
`45
`
`4
`ing glucose, hyperglycemia, impaired glucose metabolism,
`insulin resistance, obesity, diabetic complications, and the
`like.
`The term "diabetic complications" refers to conditions,
`diseases and maladies associated with diabetes including
`retinopathies, neuropathies, nephropathies, cardiomyopa(cid:173)
`thies, dermopathies, arthrosclerosis, coronary artery disease
`and other known complications of diabetes.
`The term "diastereomer" means one member of a group of
`10 two or more stereoisomers having at least two asymmetric
`carbons such that these stereoisomers are not mirror images
`of each other.
`The terms "DPP-VII, DPP-VIII, DPP-IX and FAP" mean
`respectively amino dipeptidyl peptidase VII, VIII, IX and
`fibroblast activation protein. The DPP enzymes cleave
`dipeptide moieties at the N-terminus of their protein or
`oligopeptide substrates. In particular, the term "DPP-IV"
`denotes dipeptidyl peptidase IV (EC 3.4.14.5; DPP-IV), also
`known as "CD-26." DPP-IV preferentially cleaves a dipep-
`20 tide from the N terminus of a polypeptide chain containing
`a proline or alanine residue in the penultimate position.
`The term "enantiomer" means one member of a pair of
`stereoisomers having the same molecular structure and at
`least one asymmetric carbon such that the stereoisomers of
`25 the pair are the mirror images of each other. If the enanti(cid:173)
`omer contains two or more asymmetric carbons, the enan(cid:173)
`tiomeric pair will have opposing asymmetry at each asym(cid:173)
`metric carbon.
`The term "group that can be hydrolyzed to a hydroxyl" as
`30 used herein refers to an ester group formed from the com(cid:173)
`bination of an aliphatic or aromatic alcohol or dial and a
`boronic acid.
`The term "inhibitor" (and its corresponding verb and
`gerund) means a compound that will reversibly, irreversibly
`35 or temporarily interact with an enzyme so as to reduce,
`modifY, slow down or block its enzymatic activity upon its
`normal substrate. The interaction may occur within or at the
`enzymatic site or at an allosteric site associated with the
`enzyme.
`The term "N-protecting group" or "N-protected" as used
`herein refers to those groups intended to protect the N-ter(cid:173)
`minus of an amino acid or peptide or to protect an amino
`group against undesirable reactions during synthetic proce(cid:173)
`dures. Commonly used N-protecting groups are disclosed in
`T.W. Greene, P. G. Wuts, "Protective Groups In Organic
`Synthesis, 3rd Ed." (John Wiley & Sons, New York (1999)),
`which is hereby incorporated by reference. N-protecting
`groups include acyl groups such as formyl, acetyl, propio(cid:173)
`nyl, pivaloyl,
`t-butylacetyl, 2-chloroacetyl, chloracetyl,
`50 2-bromoacetyl, trifluoroacetyl, trichloracetyl, phthalyl, o-ni(cid:173)
`trophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chloroben(cid:173)
`zoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl
`groups such as benzenesulfonyl, p-toluenesulfonyl and the
`like; carbamate forming groups such as benzyloxycarbonyl,
`55 p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl,
`p-nitrobenzyloxycarbonyl,
`2-nitrobenzyloxycarbonyl,
`p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycar(cid:173)
`bonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxy(cid:173)
`benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-
`60 4,5-dimethoxybenzyloxycarbonyl,
`3,4,5-
`trimethoxybenzyloxycarbonyl,
`1-(p-biphenylyl)-1-
`methylethoxycarbonyl,
`aa-dimethyl-3,5-
`dimethoxvbenzyloxvcarbonyl,
`benzhydryloxycarbonyl,
`t-butyloxycarbonyl, diisopropy lmethoxycarbony I, isopropy-
`65 loxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxy(cid:173)
`carbonyl, 2,2,2,-trichioroethoxycarbonyl, phenoxycarbonyl,
`4-nitrophenoxycarbonyl,
`fluorenyl-9-methoxycarbonyl,
`
`DEFINITIONS
`
`The term "absolute configuration" in connection with an
`asymmetric carbon is determined by considering the tetra(cid:173)
`hedral shape of the asymmetric carbon bonds, assigning a
`priority of 1 through 4 to each of the groups bound to the
`asymmetric carbon with the group having the highest atomic
`number having the first priority. If the tetrahedron is viewed
`from a side remote from group 4, an R absolute configura(cid:173)
`tion is assigned when groups 1-3 are in a clockwise arrange(cid:173)
`ment and an S absolute configuration is assigned when
`groups 1-3 are in a counterclockwise arrangement.
`The term "asymmetric carbon" means a carbon atom
`covalently bound to four different groups.
`The term "beta cell degeneration" is intended to mean loss
`of beta cell function, beta cell dysfunction, and death of beta
`cells, such as necrosis or apoptosis of beta cells.
`The term "Diabetes Mellitus and related conditions"
`refers to Type 1 diabetes, Type 2 diabetes, gestational
`diabetes, MODY, impaired glucose tolerance, impaired fast-
`
`Boehringer Ex. 2013
`Mylan v. Boehringer Ingelheim
`IPR2016-01566
`Page 5
`
`

`
`US 7,317,109 B2
`
`5
`
`5
`cyclo(cid:173)
`adamantyloxycarbonyl,
`cyclopentyloxycarbonyl,
`hexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl
`groups such as benzyl, triphenylmethyl, benzyloxymethyl
`and the like; and silyl groups such as trimethylsilyl and the
`like. Preferred N-protecting groups are formyl, acetyl, ben-
`zoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, 9-fluo(cid:173)
`renylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc)
`and benzyloxycarbonyl (Cbz).
`The term "optically active" means an organic compound
`containing at least one asymmetric carbon such that a 10
`solution of the organic compound will rotate plane polarized
`light.
`The term "optically active mixture" means a mixture of
`optically active compounds in solution that will rotate plane
`polarized light. The optically active mixture may be a 15
`mixture of diastereomers or an unequal mixture of enanti(cid:173)
`omers.
`The term "pharmaceutical salt" means a salt with an
`inorganic base, organic base (including basic amino acids),
`inorganic acid, and organic acid (including acidic amino 20
`acids). Included as examples of inorganic bases are alkali
`metals such as lithium, sodium or potassium; alkaline earth
`metals such as calcium and magnesium or aluminum; and
`ammonia. Included as examples of organic bases are trim(cid:173)
`ethylamine, triethylamine, pyridine, picoline, ethanolamine, 25
`diethanolamine, and triethanolamine. Included as examples
`of inorganic acids are the instant invention includes, for
`example, hydro-halogen acids such as hydrochloric acid,
`hydroboric acid, nitric acid, sulfuric acid, and phosphoric
`acid. Included as examples of organic acids are mono, di and 30
`tri carboxylic or sulfonic acids of 1 to 20 carbons, optionally
`containing I to 6 hydroxyl groups. Included as examples of
`basic amino acids are arginine,
`lysine and ornithine.
`Included as examples of acidic amino acids are aspartic acid
`and glutamic acid. Further examples of pharmaceutically 35
`acceptable salts include the pharmaceutically acceptable
`salts listed in Journal of Pharmaceutical Science, 66, 2
`(1977) which are known to the skilled artisan.
`The term "prodrug" means a pharmaceutically acceptable
`compound that will convert to the active ingredient or an 40
`active metabolite thereof upon administration of the prodrug
`to a living organism, preferably a mmal, more preferably
`a human. The conversion may occur by enzymatic action,
`chemical hydrolysis, oxidation, reduction or any other in
`vivo physiological process for chemical or biochemical 45
`reaction.
`The term "racemic mixture" means an enantiomeric pair
`of equal proportions such that they cancel each other's
`rotation of plane polarized light.
`A singular term such as "a pyrrolidine compound of the
`invention" includes the plural such as the various species of
`the pyrrolidine compound of the invention as well as mix(cid:173)
`tures thereof. A plural term such as "pyrrolidine compounds
`of the invention" includes the individual species as well as
`the plural indicated by this term, and also mixtures thereof. 55
`The term "selectivity ratio" refers to the IC50 value
`generated in a biochemical assay measuring inhibition of
`DPP-IV compared to the IC50 value generated in a biochemi-
`cal assay measuring inhibition of another DPP family mem(cid:173)
`ber (e.g. DPP-VII, DPP-VIII, DPP-IX or FAP) whereby the 60
`ratio is obtained by dividing the IC50 value of DPP-VII,
`DPP-VIII, DPP-IX or FAP by the IC50 value for DPP-IV.
`The term "solvate" means a solid, crystalline form of a
`compound which also incorporates molecules of a solvent
`into the crystal structure. Organic solvents as well as water 65
`are included. Another description of a water solvate is a
`hydrate or hydrated form.
`
`6
`The term "stereoisomer" means one of the absolute con(cid:173)
`figurations of a single organic molecule having at least one
`asymmetric carbon. Included within the definition of a
`stereoisomer are enantiomers and diastereomers. One stere(cid:173)
`oisomer has one absolute configuration about each of the
`asymmetric carbons of the organic molecule. An organic
`molecule with one asymmetric carbon presents two stereoi(cid:173)
`somers. An organic molecule with two asymmetric carbons
`presents four stereoisomers. An organic molecule with three
`asymmetric carbons presents eight stereoisomers. Projecting
`plane polarized light through a solution containing one
`stereoisomer will cause rotation of the polarized plane.
`The term "stereomeric mixture" means a mixture of two
`or more stereoisomers and includes enantiomers, diastere(cid:173)
`omers and combinations thereof. The stereomeric mixture
`may or may not be optically active.
`The term "stereomeric purity" at a given percentage
`means that the designated stereoisomer predominates at that
`given percentage in a mixture of stereoisomers.
`Unless otherwise specifically stated, the definitions of
`terms for chemical groups, functional groups, moieties and
`chemical reactions described herein follow the definitions
`provided in such organic chemistry textbooks and treatises
`as "Basic Principles of Organic Chemistry", Roberts and
`Caserio, W.A. Benjamin & Co. New York, N.Y., 1965;
`"Advanced Organic Chemistry", 4'h edition, Jerry March,
`Wiley Interscience, New York, N.Y. 1992; T. W. Greene, P.
`G. Wuts, "Protective Groups In Organic Synthesis, 3rd Ed."
`(John Wiley & Sons, New York (1999), and Hawley's
`Condensed Chemical Dictionary, 11th Ed., Sax and Lewis,
`Van Nostrand, Reinhold, New York, N.Y., 1987. Moreover,
`the definitions for stereochemical terms are based upon
`"Stereochemistry of Carbon Compounds", Ernest Eliel,
`McGraw-Hill publisher, New York, N.Y. 1962. The disclo(cid:173)
`sures of these text books are incorporated herein by refer(cid:173)
`ence.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`A pyrrolidinylaminoacetyl pyrrolidine boronic acid com(cid:173)
`pound of the invention (pyrrolidine compound of the inven(cid:173)
`tion) has the linear or cyclic isomer structure depicted by
`formulas I and V above. All stereoisomers, stereomeric
`mixtures, pharmaceutically acceptable salts, solvates and
`prodrugs are included as embodiments of the "pyrrolidine
`compounds of the invention" (which is also termed "pyrro(cid:173)
`lidine compound" or "pyrrolidine compounds" herein). A
`pharmaceutical composition including a pyrrolidine com-
`50 pound of the invention and a pharmaceutically acceptable
`pharmaceutical carrier is an additional aspect of the inven(cid:173)
`tion. Also included is a pharmaceutical combination of a
`pyrrolidine compound of the invention and a second medi(cid:173)
`cament known to be useful in the treatment of malconditions
`characterized by impaired glycemic control, especially Dia(cid:173)
`betes Mellitus and related conditions. A pharmaceutical
`combi