HETEROCYCLIC BORONIC ACID COMPOUNDS

Dipeptidyl peptidase IV (DPP-IV)-inhibiting compounds are provided that have formula I: wherein n is 1 to 3; X is CH2; S; O; CF2 or C(CH3)2; Z is H; halogen; hydroxyl; (C1-6)alkoxy; (C1-12)alkyl; (C3-12)cycloalkyl; phenyl; or heteroaryl; where the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; optionally, X together with an adjacent ring carbon and Z form a fused cyclopropyl; and optionally, one of the bonds in the ring containing X is a double bond; and CRiRii, R1, R2, R3, R4 and R5 are as described herein.

Skip to: Description  ·  Claims  · Patent History  ·  Patent History
Description
RELATED APPLICATIONS

This application is a Divisional application under 37 C.F.R. 1.53(b) of U.S. application Ser. No. 10/514,575, filed Nov. 15, 2004, which is a National Stage Filing under 35 U.S.C. 371 of International Application No. PCT/US2004/037820, and published on May 26, 2005 as WO 2005/047297, which claims priority to U.S. Provisional Application Ser. No. 60/519,566, filed Nov. 12, 2003, which is related to U.S. Provisional Application Ser. No. 60/557,011, filed Mar. 25, 2004, and to U.S. Provisional Application Ser. No. 60/592,972, filed Jul. 30, 2004, all of which applications and publication are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to boronic acid compounds and their use as inhibitors of post-proline/alanine cleaving amino-dipeptidases. The invention also relates to methods of employing such inhibitors to treat DPP-related diseases. Thus, the invention has applications in the medicinal chemical, pharmacological, and medical arts.

BACKGROUND OF THE INVENTION

Dipeptidyl peptidases (DPP) are a family of serine protease that belongs to a group of post-proline/alanine cleaving amino-dipeptidases. While the physiological role of DPPs have not been fully elucidated, they have been implicated in a number of disease states. For example, DPP-IV catalyzes the release of an N-terminal dipeptide only from proteins with N-terminal penultimate proline or alanine and DPP-IV is believed to play an important role in impaired fasting glucose (IFG) and diabetes. In particular, DPP-IV has been implicated in the control of glucose metabolism because its substrates include the insulinotropic hormones, glucagon like peptide-1 (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 GLP-1 and GIP, resulting in higher plasma concentrations of these hormones, increased insulin secretion and, therefore, improved glucose tolerance. Therefore, such inhibitors have been proposed for the treatment of patients with type II diabetes, a disease characterized by decreased glucose tolerance and insulin resistance.

Accordingly, a need exists for compounds that are useful for inhibiting DPPs such as DPP-IV.

SUMMARY OF THE INVENTION

The present invention provides DPP inhibitors that are effective in treating conditions that may be regulated or normalized by inhibition of DPPs. More particularly, the invention relates to boronic acid-containing heterocycles and their derivatives that inhibit DPP-IV.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds of formula I:
including all enantiomers, diastereoisomers, solvates, hydrates and pharmaceutically acceptable salts thereof, wherein:

n is 1 to 3;

X is CH2; S; O; CF2 or C(CH3)2;

Z is H; halogen; hydroxyl; (C1-6)alkoxy; (C1-12)alkyl; (C3-12)cycloalkyl; phenyl; or heteroaryl; where the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;

R7 is halogen; (C1-10)alkyl; (C1-10)alkoxy; (C1-10)alkylamino; (C1-10) dialkylamino; benzyl; benzyloxy; hydroxyl(C1-6)alkyl; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyamino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl;

optionally, X together with an adjacent ring carbon and Z form a fused cyclopropyl; and

optionally, one of the bonds in the ring containing X is a double bond;

R1 and R2 independently or together are hydrogen; a boronic acid protecting group; or a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids; and

CRiRii may be present or absent, and

when CRiRii is present, then

    • Ri, Rii, R3, R4 and R5 are selected from (aa) or (bb):
    • (aa) Ri, Rii, R3 and R4 are hydrogen; and R5 is hydrogen, (C1-12)alkyl or (C3-12) cycloalkyl;
    • (bb) Ri, Rii, R3, R4 and R5 are independently hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl,

or alternatively,

when CRiRii is absent, then R3, R4 and R5 are selected from (cc), (dd) or (ee):

    • (cc) R3 and R4 are hydrogen; and
      • R5 is
        • a) hydrogen, provided that R5 is not hydrogen when n is 1, X is CH2, and Z is H;
        • b) (C1-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12)cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions;
        • R6 is (C1-6)alkyl; (C1-6)alkoxy; cycloalkyl; carboxy; acetamido; cyano; nitro; halogen; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl; trifluoromethyl; trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; amino, where the amino group is optionally mono- or independently plurisubstituted with R8; —SOR8; —SO2R8; —COR8; —CO2R8, —CONHR8; —CON(R8)2; —OR8; or —S—R8;
        • R7 is halogen; (C1-10)alkyl; (C1-10)alkoxy; (C1-10)alkylamino; (C1-10) dialkylamino; benzyl; benzyloxy; hydroxyl(C1-6)alkyl; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyamino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl;
        • R8 is (C1-10)alkyl; (C2-10)alkenyl; (C2-10)alkynyl; (C3-10)cycloalkyl; (C5-10)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
        • c) aryl optionally fused to a (C3-10)cycloalkyl; or heteroaryl optionally fused to a (C3-10)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
        • d) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH2)j adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4-pentylbicyclo[2.2.2]oct-1-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (C1-8)alkyl, (C1-8)alkoxy, (C1-8)alkanoyloxy, or R9R10N—CO—O—, where R9 and R10 are independently (C1-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (C1-8)alkyl, (C1-8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3-6)alkylene;
        • e) R11(CH2)p— where R11 is 2-oxopyrrolidinyl; (C1-6)alkoxy; phenyl; phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (C1-4)alkyl, (C1-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono- or independently plurisubstituted with (C1-8)alkyl; and p is 0 to 3;
        • R12 is halogen; trifluoromethyl; cyano; nitro; (C1-6)alkyl; (C1-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
        • f) (R13)2CH(CH2)q—, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R12; and q is 0 to 3;
        • g) a group of the formula:
          where R14 and R15 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; (C3-12)cycloalkyl ring; (C3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and r is 2 to 6;
    • h) a group of the formula:
      where R16 and R17 are each independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C3-12)cycloalkyl ring; and s is 1 to 6;
    • i) a group of the formula:
      wherein R18 and R19 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R2; or wherein R18 and R19 together with the N form an (N, C3-12) heterocycloalkyl ring containing the nitrogen atom; and each t is independently 0 to 6; and u is 0 to 3;
    • j) a group of the formula:
      (phenyl-CH2—C(CH3)2—),
      where the phenyl group is optionally mono- or independently plurisubstituted with R12;
      ; or
    • k) a group of the formula:
      where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; each t is independently 0 to 6; and u is 0 to 3; and,
      wherein a bond containing a wavy line signifies a point of attachment;
    • (dd) R3, R4 and R5 are independently hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl or aralkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, arylamino, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl, provided that when n is 1, X is CH2, the ring containing X is saturated, and Z, R3 and R5 are H, R4 is not a side chain of a naturally occurring α-amino acid, and provided that when n is 1, X is CH2, the ring containing X is saturated, and Z and R5 are H, R3 and R4 are not both methyl; or,
    • (ee) R3 is hydrogen, and R4 and R5 together with the atoms to which they are attached form a 4 to 8 membered heterocyclic ring of 3 to 7 carbons and 1 nitrogen,
      wherein the heterocyclic ring carbon atoms other than the carbon connected to N and R4 have the formula —(CR22R23)m— wherein m is 2 to 6, and R22 and R23 are independently hydrogen, hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, halo, amino, substituted amino, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, alkylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, alkoxycarbonyl, aryloxycarbonyl, or alkylaminocarbonylamino; and, optionally the heterocyclic ring has an aryl, heteroaryl or a 3 to 7 membered cycloalkyl ring fused thereto, provided that when n is 1, X is CH2, the ring containing X is saturated, and Z and R3 are H, then R4 and R5 together are not —(CH2)2— or —(CH2)3—.

Compounds of formula I also include those wherein X is CH2; the ring containing X is saturated; CRiRii is absent, R1, R2 are hydrogen; and R3, R4 and R5 have the subgeneric designations given by foregoing cause (cc)b). In some such embodiments, R5 is a (C1-12)alkyl or (C3-12)cycloalkyl, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, 1-cyclohexylethyl, or adamantyl.

In some embodiments of compounds of formula I, X is CH2; the ring containing X is saturated; CRiRii is absent, R1, R2 are hydrogen; and R3, R4 and R5 have the subgeneric designation given by foregoing clause (cc)d).

In other embodiments of compounds of formula I, X is CH2; the ring containing X is saturated; CRiRii is absent, R1, R2 are hydrogen; and R3, R4 and R5 have the subgeneric designation given by foregoing clause (cc)e).

In certain embodiments of compounds of formula I, X is CH2; the ring containing X is saturated; CRiRii is absent; R1, R2, are hydrogen; and R3, R4 and R5 have the subgeneric designation given by foregoing clause (cc)f).

In some embodiments of compounds of formula I, X is CH2; the ring containing X is saturated; CRiRii is absent, R1, R2 are hydrogen; R3, R4 and R5 have the subgeneric designation given by foregoing clause (cc)g.

Compounds of formula I include those wherein X is CH2; the ring containing X is saturated; CRiRii is absent, R1, R2 are hydrogen; R3, R4 and R5 have the subgeneric designation given by foregoing clause (cc)h.

Compounds of formula I wherein X is CH2; the ring containing X is saturated; CRiRii is absent, R1, R2 are hydrogen; R3, R4 and R5 have the subgeneric designation given by foregoing clause (cc)i).

In some embodiments of compounds of formula I, X is CH2; the ring containing X is saturated; CRiRii is absent, R1, R2 are hydrogen; R3, R4 and R5 have the subgeneric designation given by foregoing clause (cc)j.

In some embodiments of compounds of formula I, X is CH2; the ring containing X is saturated; CRiRii is absent, R1, R2 are hydrogen; R3, R4 and R5 have the subgeneric designation given by foregoing clause (cc)k.

A preferred subgeneric formulation of the invention when CRiRii of Formula I is absent includes compounds of Formula II having the following linear alkyl pyrrolidine formula:

In embodiments of Formula II, R3, R4 and R5 are defined as given for groups (cc), (dd) and (ee) as given above for Formula I, and R1 and R2 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 physiological pH or in biological fluids.

In such embodiments of Formula II, R5 may be alkyl, cycloalkyl, optionally mono- or independently plurisubstituted as described above.

In some embodiments of compounds of Formula II, R3 and R4 are both hydrogen.

In other embodiments of Formula II, n is 1.

Included also are compounds of formula II wherein X is CH2; the ring containing X is saturated; R1, R2, R3 and R4 are hydrogen; and R5 is a group of the formula:
where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R2; each t is independently 0 to 6; and u is 0 to 3. In some such embodiments, R5 has formula:

Another preferred subgeneric formulation of Formula I when CRiRii is present includes compounds of formula III:

wherein R1 and R2 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 physiological pH or in biological fluids; and, R3, R4, R5, Ri and Rii are the same as are designated for groups (aa) and (bb) of foregoing Formula I.

The invention also relates to methods for preparing the above-described compounds. As shown below and as described in the EXAMPLES, the compounds of formula II and III are prepared by reacting a cyclic amine (e.g., pyrrolidine or piperidine), suitably protected with a standard protecting group such as Boc-, Fmoc-, CBz- or the like, with sec-BuLi/TMEDA followed by B(OCH3)3, to provide the methyl boronic ester derivative. Acid hydrolysis of the methyl esters with 2N HCl provides the boronic acid intermediate 1. Reaction of 1 with (+) pinanediol, deprotection of the amino protecting group, and recrystallization provides the pinanediol ester 2 as an isomerically pure salt.

Intermediate 2 is useful for the synthesis of both series A and series B compounds. For example, N-acylation of 2 with chloroacetyl chloride provides the α-chloro amide 3. Treatment of 3 with Na2CO3 and cyclopentylamine, and hydrolysis of the pinanediol boronic ester, provides a compound of formula I, 4. Alternatively, coupling of intermediate 2 with N-Boc-5-phenyl-Pro using EDAC/HOBT provides amide 5. Deprotection of the amino group and hydrolysis of the boronic esters, provides a compound of formula II, 6.

This synthetic scheme is adaptable for the preparation of all the compounds of the invention, by reacting the appropriate cyclic amine (pyrrollidine, piperidine, and other cyclic amines) with sec-BuLi/B(OCH3)3, and coupling the boronic ester intermediate with the desired acid chloride or acid via routes A or B, respectively. The appropriate cyclic amine may either be commercially available or is easily synthesized through known procedures, for example, those procedures disclosed in U.S. Pat. Nos. 6,617,340; 6,432,969; 6,380,398; 6,172,081; 6,166,063; 6,124,305; 6,110,949; 6,107,317; 6,011,155; and 6,395,767, which are hereby incorporated by reference in their entirety.

Thus, another aspect of the invention provides a process for preparing the compounds of formula I:

by coupling a reactive compound of formula:
with an amine of formula: R5—NT2; optionally deprotecting the boronic acid ester; and recovering the resultant compound as a free acid or as an acid addition salt; wherein L is a leaving group. R1, R2, R3, R4, Ri, Rii, n, X, and Z are as defined herein. Preferred embodiments are those where R3 and R4 are hydrogen, L is halogen, including but not limited to Cl, and R5—NH2 is cyclopentylamine.

The compounds of the invention may be prepared in the form of pharmaceutically acceptable salts, especially acid-addition salts, including salts of organic acids and mineral acids. Examples of such salts include salts of organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like. Suitable inorganic acid-addition salts include salts of hydrochloric, hydrobromic, sulphuric and phosphoric acids and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) which are known to the skilled artisan.

The acid addition salts may be obtained as the direct products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.

The compounds of this invention may form solvates with standard low molecular weight solvents, including water to yield hydrates, using methods known to the skilled artisan.

It is to be understood that the invention extends to all of the stereoisomeric forms of the claimed compounds, including enantiomers and diastereomers, as well as the racemates.

Pharmaceutical Compositions

Pharmaceutical compositions containing a compound of the invention of the invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practise of Pharmacy, 19th Ed., 1995. The compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.

The compounds of the invention are effective for DPP-IV inhibition over a wide dosage range. For example, in the treatment of adult humans, dosages from about 0.05 to about 1000 mg, preferably from about 1 to about 500 mg, per day may be used. A typical dosage is about 10 mg to about 500 mg per day. In choosing a regimen for patients it may frequently be necessary to begin with a higher dosage and when the condition is under control to reduce the dosage. The exact dosage will depend upon the mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.

Generally, the compounds of the invention are dispensed in unit dosage form comprising from about 0.05 to about 1000 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage.

DEFINITIONS

By “substantially pure” in relation to compounds of the invention such as, but not limited to, those of formula VA and VB, it is meant that one isomer or the other, including all enantiomers, diastereoisomers, solvates, hydrates, and pharmaceutically acceptable salts thereof, represents at least 90% by weight of the composition. In some embodiments one isomer represents at least 98% by weight of the composition.

The term “boronic acid protecting group” as used herein refers to a moiety employed to block or protect the boronic acid functionality while reactions involving other functional sites of the compound are carried out. Typically, the boronic acid OH groups are protected as boronic acid esters derived from alchohols such as (+)-pinanediol; pinacol; 1,2-dicyclohexyl-ethanediol; 1,2-ethanediol; 2,2-diethanolamine; 1,3-propanediol; 2,3-butanediol, diisopropyl tartrate; 1,4-butanediol; diisopropylethanediol; (S,S,)-5,6-decanediol; 1,1,2-triphenyl-1,2-ethanediol; (2R,3R)-1,4-dimethyoxy-1,1,4,4-tetraphenyl-2,3-butanediol; methanol; ethanol; isopropanol; catechol; 1-butanol; and the like. As will be understood by those skilled in the art, alcohols having only a single hydroxy group, such as methanol, form diesters having the structure —B(OR)2 in which R is the organic moiety from the alcohol (e.g., —B(OMe)2). By comparison, diols such as pinacol form cyclic boronic diesters with —B(OH)2 in which the organic moiety (e.g., —C(Me)2—C(Me)2—)is attached to both oxygens.

The term “N-protecting group” or “N-protected” as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. 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 comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-di methyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, 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, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

The term “alkyl” or “(C1-12)alkyl”, alone or in combination, refers to linear or branched chains and may include cyclic portions, having from 1-12 (the use of 1-12 herein implies each of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, such as but not limited to, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4-methylpentyl, neopentyl, 2,2-dimethylpropyl, and the like.

The terms “(C1-10)alkyl”, “(C1-8)alkyl” and “(C1-6)alkyl”, alone or in combination, refers to linear or branched chains and may include cyclic portions, having from 1-10, 1-8, or 1-6 carbon atoms, respectively, such as but not limited to, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4-methylpentyl, neopentyl, 2,2-dimethylpropyl, and the like.

The term “(C1-4)alkyl”, alone or in combination, refers to linear or branched chains and may include cyclic portions, having from 1-4 carbon atoms, such as but not limited to, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.

The terms “(C2-12)alkenyl” and “(C2-10)alkenyl”, alone or in combination, refers to a straight or branched, unsaturated hydrocarbon chain having from 2-12 or 2-10 carbon atoms, respectively, and at least one double bond, such as, but not limited to, vinyl, 1-propenyl, allyl, isopropenyl, n-butenyl, n-pentenyl, n-hexenyl, and the like.

The terms “(C2-12)alkynyl” and “(C2-10)alkynyl”, alone or in combination, refers to an unsaturated hydrocarbon chain having from 2-12 or 2-10 carbon atoms, respectively, and at least one triple bond, such as but not limited to —C≡CH, —C≡C—CH3, —CH2C≡CH, —CH2—CH2—C≡CH, —CH(CH3)C≡CH, and the like.

The terms “(C3-12)cycloalkyl” and “(C3-10)cycloalkyl” refers to one or more saturated cyclic hydrocarbons having from 3-12 or 3-10 carbon atoms, respectively, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and the like.

The term “(C5-10)cycloalkenyl” refers to a radical of one or more cyclic hydrocarbon having at least one double bond having from 5-10 carbon atoms such as, but not limited to, cyclopentenyl, cyclohexenyl, and the like.

The term “cycloalkylene” refers to a “cycloalkyl” group which has single bonds for attachment at two different carbon atoms.

The terms “(C1-6)alkylaminocarbonyl” and “di-(C1-6)alkylaminocarbonyl” refer to straight or branched chain hydrocarbon groups having 1 to 6 carbon atoms connected to NC(═O). Exemplary alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, and the like.

The term “(C1-6)alkylcarbonyl” refers to linear or branched chain and cyclic hydrocarbon groups having 1 to 6 carbon atoms connected to C(═O). Exemplary alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, and the like.

The term (C3-8)cycloalkylcarbonyl refers to cyclic hydrocarbon groups having 3 to 8 carbon atoms connected to C(═O). Exemplary cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The terms “(C1-10)alkoxy”, “(C1-8)alkoxy” and “(C1-6)alkoxy”, alone or in combination, refers to “O” connected to alkyl, having linear or branched chains and may include cyclic portions, having from 1-10, 1-8 or 1-6 carbon atoms, respectively. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like. Examples of branched alkoxy include but are not limited to isoprpoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

The term “aryloxy” refers to an aryl group bonded to O.

The term “alkanoyl”, alone or as part of another group, refers to alkyl linked to a carbonyl group.

The term “alkylene” refers to alkyl groups which have single bonds for attachment at two different carbon atoms.

The term “alkenylene” refers to alkenyl groups which have single bonds for attachement at two different carbon atoms.

The terms “alkynylene” refers to alkynyl groups which have single bonds for attachement at two different carbon atoms.

The term “aryl” refers to monocyclic, bicyclic, or tricyclic carbocyclic aromatic ring systems having 6 to 14 carbon atoms in the ring portion. Examples of aryl groups include but are not limited to phenyl, naphthyl, biphenyl, anthracenyl, azulenyl, and the like. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems including 1,2,3,4-tetrahydro-naphthyl, indanyl and the like.

Examples of “aryl” include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), and the like.

The terms “arylalkenyl” and “arylalkynyl” alone or as part of another group refer to alkenyl and alkynyl groups as described above having an aryl substituent.

The terms “halogen” and “halo” refers to chloro, fluoro, bromo or iodo.

The term “alkylamino”, “arylamino”, or “arylalkylamino” alone or as part of another group includes any of the above alkyl, aryl or arylalkyl groups linked to a nitrogen atom.

The term “substituted amino” as employed herein alone or as part of another group refers to amino substituted with one or two substituents, which may be the same or different, such as alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl haloalkyl, hydroxyalkyl, alkoxyalkyl or thioalkyl. These substituents may be further substituted with any of the groups as set out above.

The terms “alkylthio”, “arylthio” or “aralkylthio” alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to a sulfur atom.

The term “acyl” by itself or part of another group refers to an organic radical linked to a carbonyl group; examples of acyl groups include any of the groups attached to a carbonyl, such as alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaroyl, cycloalkanoyl, cycloheteroalkanoyl, and the like.

The phrase “naturally occurring α-amino acid sidechain” refers to the moieties (sidechains) attached to the α-amino carbon in the following naturally occurring α-amino acids: glycine, alanine, 2-aminobutyric acid, valine, leucine, isoleucine, tert-leucine, serine, threonine, cysteine, asparagine, aspartic acid, glutamine, glutamic acid, phenylalanine, histidine, tryptophan, tyrosine, phenylglycine, lysine, methionine, and arginine. The side chains of these amino acids are well known in the art. For example, the α-amino acid sidechain of alanine is methyl; the sidechain of phenylalanine is benzyl; and the sidechain of tert-leucine is tert-butyl.

The term “polyhaloalkyl” refers to an “alkyl” group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl, preferably F, such as CF3CH2, CF3 or CF3CF2CH2.

The term “polyhaloalkoxy” refers to an “alkoxy” or “alkyloxy” group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl, preferably F, such as CF3CH2O, CF3O or CF3CF2CH2O.

The terms “polycyclic” and “polycycle” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, aryls, heteroaryls and/or cycloheteroalkyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are “fused rings.” Fused rings that are joined through nonadjacent atoms, are also known as “bridged” rings. Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, trifluoromethyl, cyano, or the like.

EXAMPLES

A further detailed description of the invention is given with reference to the following non-limiting examples.

Example 1 Synthesis of (2R)-boroPro-(1S,2S,3R,5S)-pinanediol ester, hydrochloride (2)

A flame dried round bottom flask equipped with a magnetic stir bar was charged with N-Boc-pyrrolidine (20 g, 117 mmol, 1 eq) and dry THF (60 mL) under a nitrogen atmosphere. The clear colorless solution was cooled to −78° C. and a solution of s-BuLi (100 mL of a 1.4 M solution in cyclohexane, 140 mmol) was added slowly over a 30 minute period. The light orange colored solution was stirred at −78° C. for 3 hours followed by treatment with B(OMe)3 (39 mL, 350 mmol) after which the cooling bath was removed and the clear colorless solution slowly warmed to 0° C. Upon reaching 0° C., the reaction was quenched with a small amount of water (˜2 mL), allowed to warm to room temp then extracted into 2 N NaOH (250 mL) and backwashed with additional EtOAc (150 mL). The aqueous phase was acidified to pH 3 by the addition of 2 N HCl and then extracted with EtOAc (3×120 mL). The organic extracts were combined and dried over Na2SO4 and concentrated to produce the free boronic acid (22.08 g, 103 mmol) as a sticky white solid in 88% yield. Without further purification the boronic acid was dissolved in tert-butyl methyl ether (150 mL) and with constant stirring (+)-pinanediol (17.5 g, 103 mmol) was added at room temperature. After 18 hr the ether was removed and the (+)-pinanediol boronic ester was purified by column chromatography (silica gel, 1:3 hexanes/EtOAc) to give a clear thick oil (26.84 g, 76.8 mmol, 76% yield, Rf=0.6 using a 2:1 hexane/ethyl acetate eluant, made visual via I2 and/or PMA stain). Removal of the Boc protecting group was achieved by dissolving the oil in dry ether, cooling to 0° C. in an ice bath and with constant stirring dry HCl (g) was bubbled into the solution for 10 minutes. After 2 hours a white precipitate developed in the flask and the ether and excess HCl were removed in vacuo to afford the racemic HCl salt as a white solid. Crystallization and isolation of the desired isomer was performed by dissolving the HCl salt in a minimal amount of dichloromethane (250 mL) with gentle heating to facilitate a homogenous solution followed by continuous stirring for 8 hours to yield a fluffy white precipitate that was collected by vacuum filtration, dried and then dissolved in minimal 2-propanol (˜200 mL) with gentle heating until homogenous. The alcoholic solution was stirred over night and the resulting white precipitate was collected by vacuum filtration affording isomerically pure 1 as a white solid. (7.0 g, 27 mmol, 23% yield). 1H NMR (400 MHz, D2O) δ 4.28 (d, J=8.0 Hz, 1H), 3.06 (m, 3H), 2.18 (m, 1H), 1.96 (m, 2H), 1.78 (m, 3H), 1.62 (m, 2H), 1.21 (s, 3H), 1.05 (m, 5H), 0.84 (d, J=12 Hz, 2H), 0.71 (s, 2H), 0.62 (s, 3H).

Example 2 Synthesis Of Series A Compounds: (2R)-1-(2-Cyclopentylamino-acetyl)-boroPro-OH (4)

Step 1: (2R)-1-(2-Chloroacetyl)-boroPro-(1S,2S,3R,5S)-pinanediol ester (3A).

To a solution of 2 (36.7 g, 129.3 mmol) dissolved in dry CH2Cl2 (200 mL) cooled to 0° C. was added chloroacetyl chloride (12.34 mL, 155.2 mmol) under a blanket of N2. To this was slowly dripped 4-methylmorpholine (42.4 mL, 182 mmol) to give an almost clear light orange solution that was warmed to room temp. After 30 minutes the solution was cooled again to 0° C. and 200 mL of a 0.2N solution of HCl was added and the organic layers separated, dried and concentrated to give a dark red oil that was a single spot by TLC (2:1 hex/EtOAc, Rf=0.22, made visual via I2 and/or PMA stain) and was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ0.80 (s, 3H), 1.25 (m, 1H), 1.26 (s, 3H), 1.42 (s, 3H), 1.75-1.96 (m, 4H), 1.98-2.10 (m, 3H), 2.12-2.20 (m, 1H), 2.29-2.35 (m, 1H), 3.12-3.16 (m, 1H), 3.47-3.53 (m, 1H), 3.58-3.63 (m, 1H), 3.97-4.05 (q, 2H), 4.30-4.32 (d, 1H).

Step 2: (2R)-1-(2-Cyclopentylamino-acetyl)-boroPro-(1S,2S,3R,5S)-pinanediol ester (3B).

Compound 3A was dissolved in dry THF (˜150 mL) followed by addition of K2CO3 (35 g) and cooled to 0° C. before addition of cyclopentylamine (21.93 g, 258 mmol). The reaction mixture was then allowed to warm to room temperature and stirred overnight. TLC indicated all starting material was consumed. The mixture was filtered through a celite and silica pad, washed with 5% MeOH in CH2Cl2 (200 mL) and concentrated to yield a sticky, light orange solid. The red sticky solid was dissolved in CH2Cl2 (150 mL) followed by addition of Et2O (˜200 mL) and the solution was stirred overnight. The resulting milky white solution was then filtered and the precipitate was washed with cold EtOAc (2×60 mL) and hexane (2×50 mL) and dried to give 3B (28.92 g, 120.5 mmol) as a fluffy white solid. The dark red mother liquor filtrate was concentrated and subjected to the previous recrystallization conditions to obtain a second crop of 3B (6.17 g, 25.7 mmol) for a combined overall yield of 3B (35.09 g, 93.8 mmol) of 73% yield. Rf=0.45 (10% MeOH in CH2Cl2). 1H NMR (400 MHz, CDCl3) δ 4.18 (d, 1H), 3.95 (d, J=16 Hz, 1H), 3.6 (d, J=16 Hz, 1H), 3.46 (m, 3H), 2.74 (m, 1H), 2.36 (m, 1H), 2.16 (m, 2H), 2.04 (m, 4H), 1.90 (s, 1H), 1.74 (m, 6H), 1.61 (s, 1H), 1.46 (m, 2H), 1.34 (s, 3H), 1.30 (s, 3H), 0.88 (s, 3H).

Step 3: (2R)-1-(2-Cyclopentylamino-acetyl)-boroPro-OH (4)

To a solution of 3B (40.59 g, 108.5 mmol) in H2O (200 mL, adjusted to pH 2 by addition of 2 N HCl) was added hexane (200 mL) and phenyl boronic acid (13.37 g, 109.5 mmol) and the bi-phasic mixture was stirred vigorously. The hexane layer was periodically removed and replaced with fresh hexane 6 times over a 24-hour period. The aqueous layer was separated and applied to a Dowex 50-X2-100 ion exchange column (H+ form) and eluted with water until the eluate was neutral. Elution with aqueous ammonium hydroxide (2 wt %) followed by lyophilization of the appropriate fractions yielded 4 (23.91 g, 99.6 mmol) as a white crystalline solid in a 92% yield. 4-TFA salt 1H NMR (400 MHz, D2O) δ 3.88 (dd, J=8.0 Hz, 2H), 3.54 (m, 1H), 3.42 (m, 1H), 3.28 (m, 1H), 2.96 (m, 1H), 1.96 (m, 4H), 1.85 (m, 2H), 1.63 (m, 7H); MS (ESI) m/z 223 (M+H—H2O)+.

Example 3 Synthesis of 1-(2-Cyclopropylamino-acetyl)-pyrrolidine-(2R)-boronic acid (A2)

The title compound was prepared according to the procedure of Example 2 using appropriate starting materials. 1H NMR (D2O) δ 4.08 (dd, J=12 Hz, 2H), 3.54 (m, 1H), 3.38 (m, 1H), 3.07 (m, 1H), 2.26 (m, 1H), 2.09 (m, 2H), 1.94 (m, 1H), 1.71 (m, 1H), 0.88 (s, 4H); MS (ESI) m/z 195.13 (MH+—H2O).

Example 4 Synthesis of 1-[2-(3-Hydroxy-adamantan-1-ylamino)-acetyl]-pyrrolidine-(2R)-boronic acid (A3)

The title compound was prepared according to the procedure of Example 2 using appropriate starting materials. 1H NMR (D2O) δ 3.94 (d, J=8 Hz, 2H), 3.54 (m, 1H), 3.40 (m, 1H), 3.09 (m, 1H), 2.41 (s, 2H), 2.09 (m, 3H), 1.93 (m, 2H), 1.87 (m, 7H), 1.71 (m, 6H), 1.56 (m, 2H); MS (ESI) m/z 305.21 (MH+—H2O).

Example 5 Synthesis of 1-(5R-Phenyl-pyrrolidine-2S-carbonyl)-pyrrolidine-(2R)-boronic acid (6)

Step 1: N-Boc-5-phenylPro-(2R)-boroPro-(1S,2S,3R,5S)-pinanediol ester (5):

To an ice-cooled (0° C.) solution of N-Boc-5-phenyl-Pro-OH (0.84 mmol) in dry CH2Cl2 was added EDAC (174 mg, 0.91 mmol) and HOBt (105 mg, 0.775 mmol). The reaction was stirred at 0° C. for 15-minutes and then 2 (200 mg, 0.7 mmol) and N-methyl morphiline (0.25 mL, 2.1 mmol) was added and the reaction was slowly warmed to room temperature and the reaction continued for 8 hours. The coupling reaction was then quenched with the addition of NaHCO3 (10 mL), extracted into EtOAc (2×15 mL), washed with brine (15 mL), dried over Na2SO4, concentrated and further purified via column chromatography (silica gel, eluted with a gradient of EtOAc in hexanes, 30-50%) to afford 5 (320 mg, 0.62 mmol, 88%) as an off-white solid.

Step 2: 1-(5R-Phenyl-pyrrolidine-2S-carbonyl)-pyrrolidine-(2R)-boronic acid (6):

An ice-cooled solution of 5 (320 mg, 0.62 mmol) in dry ether was saturated with dry HCl (g) and allowed to stir for 1-hour. The solution was then concentrated under vacuum to afford a sticky white solid that was taken up in H2O (10 mL, adjusted to pH 2 by addition of 2 N HCl) and hexane (10 mL) and phenyl boronic acid (74 mg, 0.62 mmol) and the bi-phasic mixture was stirred vigorously. The hexane layer was periodically removed and replaced with fresh hexane 6 times over a 24-hour period. The aqueous layer was separated and applied to a Dowex 50-X2-100 ion exchange column (H+ form) and eluted with water until the eluate was neutral. Elution was continued with aqueous ammonium hydroxide (2 wt %) and the appropriate fractions were lyophilized to afford the free boronic acid B1 (76 mg, 0.26 mmol) as an amorphous white solid. 1H NMR (D2O) δ 7.46 (m, 5H), 3.65 (m, 1H), 3.44 (m, 1H), 3.04 (m, 1H), 2.54 (m, 1H), 2.38 (m, 2H), 2.20 (m, 1H), 2.06 (m, 2H), 1.86 (m, 1H), 1.66 (m, 1H); MS (ESI) m/z 271 (MH+—H2O).

Example 6 Synthesis of 1-(Piperidine-2S-carbonyl)-pyrrolidin-(2R)-boronic acid (B2)

The title compound was prepared according to the procedure of Example 5 using appropriate starting materials. 1H NMR (D2O) δ 4.07 (m, 1H), 3.61 (m, 1H), 3.34 (m, 2H), 2.94 (m, 2H), 2.16 (m, 1H), 2.03 (m, 2H), 1.87 (m, 3H), 1.56 (m, 4H); MS (ESI) m/z 209 (MH+—H2O).

Example 7 Synthesis of 1-(2,3-Dihydro-1H-indole-2S-carbonyl)-pyrrolidine-(2R)-boronic acid (B3)

The title compound was prepared according to the procedure of Example 5 using appropriate starting materials. 1H NMR (D2O) δ 4.54 (m, 1H), 3.73 (m, 1H), 3.58 (m, 1H), 3.34 (m, 1H), 2.48 (m, 1H), 2.37 (m, 1H), 2.06 (m, 3H), 1.83 (m, 3H), 1.58 (m, 4H), 1.32 (m, 4H); MS (ESI) m/z 249 (MH+—H2O).

Example 8 Synthesis of 1-(4S-Phenyl-pyrrolidine-2S-carbonyl)-pyrrolidine-(2R)-boronic acid (B4)

The title compound was prepared according to the procedure of Example 5 using appropriate starting materials. 1H NMR (D2O) δ 7.34 (d, J=13 Hz, 2H), 7.27 (m, 3H), 4.79 (m, 1H), 3.83 (m, 1H), 3.59 (m, 1H), 3.34 (m, 2H), 3.06 (m, 1H), 2.53 (m, 2H), 2.08 (m, 2H) 1.77 (m, 1H), 1.64 (m, 1H); MS (ESI) m/z 271 (MH+—H2O).

Example 9 Synthesis of Series C Compounds: (2R)-1-[(2S,4S)-4-Amino-pyrrolidine-2-carbonyl]-boroPro-OH (15)

Step 1: (2R)-1-[(2S,4S)-1-tert-Butoxycarbonyl-4-benzyloxycarbonylamino-pyrrolidine-2-carbonyl]-boroPro-(1S,2S,3R,5S)-pinanediol ester (13)

The protocol described for the synthesis of 11 was followed employing (2S,4S)-Fmoc-4-amino-1-boc-pyrrolidine-2-carboxylic acid (628 mg, 2.2 mmol) in place of azetidine-1,2-dicarboxylic acid 1-tert-butyl ester. Compound 13 was obtained as a clear colorless oil that was used in the next step without further purification.

Step 2: (2R)-1-[(2S,4S)-1-tert-Butoxycarbonyl-4-amino-pyrrolidine-2-carbonyl]-boroPro-(1S,2S,3R,5S)-pinanediol ester (14)

To a solution of 13 dissolved in DCM (10 ml) was added diethyl amine (5 ml) at once and the resulting colorless solution was stirred overnight at room temperature. The reaction was evaporated to dryness and additional DCM was added followed by evaporation once again to dryness. The resulting oil was purified by column chromatography (silica gel, eluted with a gradient of 2.5 to 5% MeOH in DCM, made visible by 12 and/or PMA) to give 14 as a clear colorless oil in a 48% yield over 2 steps.

Step 3: (2R)-1-[(2S,4S)-4-Amino-pyrrolidine-2-carbonyl]-boroPro-OH (15)

The protocol described above for the N-Boc deprotection and pinanediol ester hydrolysis in the synthesis of compound 12 was applied to 14. Compound 15 was obtained as a white solid. 15.TFA salt 1H-NMR (500 MHz, D2O) δ 4.42 (dd, 1H), 3.87 (m, 1H), 3.5 (dd, 1H), 3.28 (m, 2H), 3.07 (m, 1H), 2.73 (m, 1H), 2.64 (m, 1H), 1.86 (m, 1H), 1.72 (br m, 2H), 1.55 (br m, 2H), 1.34 (m, 2H). MS m/z (rel intensity) 228 (M+1) (55), 210 (M+1—H2O) (95).

Example 10 Synthesis of Series D Compounds: (2R)-1-[(2S)-4-Methanesulfonyl-piperazine-2-carbonyl]-boroPro-OH (19)

Step 1: (2R)-1-[(2S)-1-tert-Butoxycarbonyl-4-benzyloxycarbonyl-piperazine-2-carbonyl]-boroPro-(1S,2S,3R,5S)-pinanediol ester (16)

The protocol described above for the synthesis of 11 was followed employing (2S)—N-1-Boc-N-4-Cbz-2-piperazine carboxylic acid (1 g, 2.6 mmol) in place of azetidine-1,2-dicarboxylic acid 1-tert-butyl ester. Compound 16 (690 mg, 1.5 mmol) was obtained in 57% yield as an oil after silica gel column chormatography. MS m/z (rel intensity) 618 (M+23)+(17), 596 (M+1)+(100), 496 (38).

Step 2: (2R)-1-[(2S)-1-tert-Butoxycarbonyl-piperazine-2-carbonyl]-boroPro-(1S,2S,3R,5S)-pinanediol ester (17)

To a solution of compound 16 (314 mg, 0.53 mmol) in MeOH (6 mL) was added Pd/C (40 mg). The mixture was stirred under a H2 atmosphere for 2 h. Upon completion of the reaction, it was filtered through a plough of Celite. The solvents were removed under reduced pressure and the oily residue used in the next step without further purification. MS m/z (rel intensity) 462 (M+1)+(100), 406 (12), 362 (11).

Step 3: (2R)-1-[(2S)-1-tert-Butoxycarbonyl-4-methanesulfonyl-piperazine-2-carbonyl]-boroPro-(1S,2S,3R,5S)-pinanediol ester (18)

To a solution of compound 17 (214 mg, 0.46 mmol) in CH2Cl2 (5 mL) cooled to 0° C. was sequentially added N-methylmorpholine (204 μL, 1.9 mmol) and methanesulfonyl chloride (72 μL, 0.93 mmol). The reaction mixture was allowed to warm up to room temperature and stir for 3 hours. The reaction was then diluted with CH2Cl2 (6 ml) and water (6 mL). The organic phase was isolated and dried over MgSO4. After filtration, solvents were removed under reduced pressure. The oily residue was purified by column chromatography (silica gel) using a mixture of EtOAc/Hexanes as eluent. Compound 18 (112 mg, 0.21 mmol) was obtained in 45% yield. MS m/z (rel intensity) 562 (M+23)+(14), 540 (M+1) (100), 388 (75).

Step 4: (2R)-1-[(2S)-4-Methanesulfonyl-piperazine-2-carbonyl]-boroPro-OH (19)

The protocol described above for the N-Boc deprotection and pinanediol ester hydrolysis in the synthesis of compound 12 was applied to 18 (112 mg, 0.21 mg). Compound 19 (32 mg, 0.11 mmol) was obtained in 53% yield. 19.TFA salt 1H-NMR (500 MHz, D2O) δ 4.32 (dd, J=11.0, 3.5 Hz, 1H), 4.05 (m, 1H), 3.93 (m, 1H), 3.77 (m, 1H), 3.60 (ddd, J=10.5, 8.0, 2.5 Hz, 1H), 3.47 (ddd, J=12.5, 3.0, 3.0, 1H), 3.35 (m, 2H), 3.16 (m, 2H), 3.02 (dd, J=13.8, 11.3 Hz, 1H), 2.93 (s, 3H), 1.96 (m, 2H), 1.81 (m, 1H), 1.72 (m, 1H), 1.56 (m, 1H). MS m/z (rel intensity) 575 (12), 328 (M+23)+(6), 288 (M−17) (100).

Example 11

Using the procedures illustrated above, the following compounds in the Table were prepared and characterized using liquid chromatography-mass spectroscopy (LC-MS).

TABLE Compound No. Series Structure LC-MS 22 A 255 (M + 1)(13), 237 (100) 23 A 227 (M + 1)(10), 209 (100) 24 A 229 (M + 1)(18), 211 (100) 25 A 215 (M + 1)(12), 197 (100) 26 A 263 (M + 1)(5), 245 (100) 27 A 277 (M + 1)(4), 259 (100) 28 A 283 (M + 1)(22), 265 (100) 29 A 277 (M + 1)(5), 259 (100) 30 A 283 (M + 1)(21), 265 (100) 31 A 269 (M + 1)(16), 251 (100) 43 A 271 (M + 1)(100), 253 (16) 44 A 270 (M + 1)(100), 252 (17) 47 A 721 (10), 361 (M + 1)(100) 48 A 285 (M + 1)(100), 267 (12) 95 B 201 (M + 1)(100), 183 (22) 96 B 255 (M + 1)(100), 237 (100) 97 B 187 (M + 1)(5), 169 (100) 98 B 243(M + 1)(5), 225 (71) 99 B 449(5), 243(M + 1)(7), 225 (100) 100 B 223(M + 23)(3), 183(48) 101 B 223(M + 23)(4), 183(10) 102 C 228(M + 1)(55), 210 (M − 17)(95) 103 C 210(M − 17)major, 228(M + 1)minor 104 C 210(M − 17)major, 228(M + 1)minor 105 D 575(12), 328 (M + 23)(6), 288 (100) 106 D 452 (M + 1)(3), 434 (100) 107 D 368 (M + 1)(2), 350 (100) 108 D 428 (M − 17)(100) 109 D 386 (M − 17)(100) 110 D 436 (M + 1)(10), 418 (100) 111 D 436 (M + 1)(4), 418 (100) 112 D 627 (25), 332 (M + 1)(10), 314 (100) 113 D 368(M + 1)(38), 350 (100) 114 D 350 (M − 17)(100) 332 (22) 115 D 332(M + 1)(4), 314 (93) 116 D 338(M + 1)(3), 320 (98) 117 D 332(M + 1)(27), 314 (100) 118 D 338 (M + 1)(21), 320 (100) 130 G 623 (28), 312 (M + 1) (100), 294 (30) 131 G 819 (20), 410 (100) 132 G 374 (M + 1)(100), 356 (67) 133 G 759 (57), 380 (M + 1)(100), 362 (64)

While the invention has been described and exemplified in sufficient detail for those skilled in this art to make and use it, various alternatives, modifications, and improvements will be apparent to those skilled in the art without departing from the spirit and scope of the claims.

All patents and publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.

In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group. For example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, claims for X being bromine and claims for X being bromine and chlorine are fully described.

Claims

1. A pyrrolidine compound of formula I: including all enantiomers, diastereoisomers, solvates, hydrates and pharmaceutically acceptable salts thereof, wherein:

n is 1 to 3;
X is CH2; S; O; CF2 or C(CH3)2;
Z is H; halogen; hydroxyl; (C1-6)alkoxy; (C1-12)alkyl; (C3-12)cycloalkyl; phenyl; or heteroaryl; where the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
R7 is halogen; (C1-10)alkyl; (C1-10)alkoxy; (C1-10)alkylamino; (C1-10) dialkylamino; benzyl; benzyloxy; hydroxyl(C1-6)alkyl; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyamino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl;
optionally, X together with an adjacent ring carbon and Z form a fused cyclopropyl; and
optionally, one of the bonds in the ring containing X is a double bond;
R1 and R2 independently or together are hydrogen; a boronic acid protecting group; or a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids; and
CRiRii may be present or absent, and
when CRiRii is present, then Ri, Rii, R3, R4 and R5 are selected from (aa) or (bb): (aa) Ri, Rii, R3 and R4 are hydrogen; and R5 is hydrogen, (C1-12)alkyl or (C3-12) cycloalkyl; (bb) Ri, RiiR3, R4 and R5 are independently hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl,
or alternatively,
when CRiRii is absent, then R3, R4 and R5 are selected from (cc), (dd) or (ee): (cc) R3 and R4 are hydrogen; and R5 is a) hydrogen, provided that R5 is not hydrogen when n is 1, X is CH2, and Z is H; b) (C1-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; (C3-12)cycloalkyl; or (C3-12)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions; R6 is (C1-6)alkyl; (C1-6)alkoxy; cycloalkyl; carboxy; acetamido; cyano; nitro; halogen; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl; trifluoromethyl; trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; amino, where the amino group is optionally mono- or independently plurisubstituted with R8; —SOR8; —SO2R8; —COR8; —CO2R8, —CONHR8; —CON(R8)2; —OR8; or —S—R8; R7 is halogen; (C1-10)alkyl; (C1-10)alkoxy; (C1-10)alkylamino; (C1-10) dialkylamino; benzyl; benzyloxy; hydroxyl(C1-6)alkyl; hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy; trifluoromethylthio; N-hydroxyamino; cyano; carboxy; acetamido; hydroxy; sulfamoyl; sulfonamido; or carbamoyl; R8 is (C1-10)alkyl; (C2-10)alkenyl; (C2-10)alkynyl; (C3-10)cycloalkyl; (C5-10)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; c) aryl optionally fused to a (C3-10)cycloalkyl; or heteroaryl optionally fused to a (C3-10)cycloalkyl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; d) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH2)j adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4-pentylbicyclo[2.2.2]oct-1-yl)amine; where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (C1-8)alkyl, (C1-8)alkoxy, (C1-8)alkanoyloxy, or R9R10N—CO—O—, where R9 and R10 are independently (C1-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (C1-8)alkyl, (C1-8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3-6)alkylene; e) R11(CH2)p— where R11 is 2-oxopyrrolidinyl; (C1-6)alkoxy; phenyl; phenoxy; (C1-8)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12; where the phenoxy group is optionally mono- or independently disubstituted with (C1-4)alkyl, (C1-4)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono- or independently plurisubstituted with (C1-8)alkyl; and p is 0 to 3; R12 is halogen; trifluoromethyl; cyano; nitro; (C1-6)alkyl; (C1-6)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C1-6)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; f) (R3)2CH(CH2)q—, where R13 is phenyl; in which the phenyl groups are independently optionally mono- or independently disubstituted with R2; and q is 0 to 3; g) a group of the formula: where R14 and R15 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; (C3-12)cycloalkyl ring; (C3-12)cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R14 and R15 together form a (C3-12)cycloalkyl ring; and r is 2 to 6;
h) a group of the formula:
where R16 and R17 are each independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or R16 and R17 together form a (C3-12)cycloalkyl ring; and s is 1 to 6;
i) a group of the formula:
wherein R18 and R19 are independently hydrogen; (C1-8)alkyl; (C1-6)alkylcarbonyl; di-(C1-6)alkylaminocarbonyl; benzyl; benzothiazole; benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12; or wherein R18 and R19 together with the N form an (N, C3-12) heterocycloalkyl ring containing the nitrogen atom; and each t is independently 0 to 6; and u is 0 to 3;
j) a group of the formula:
(phenyl-CH2—C(CH3)2—),
where the phenyl group is optionally mono- or independently plurisubstituted with R12;
; or
k) a group of the formula:
where R21 is hydrogen; (C1-8)alkyl; benzyl; or phenyl; in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12; each t is independently 0 to 6; and u is 0 to 3; and,
wherein a bond containing a wavy line signifies a point of attachment;
(dd) R3, R4 and R5 are independently hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl or aralkyl; all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, arylamino, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl, provided that when n is 1, X is CH2, the ring containing X is saturated, and Z, R3 and R5 are H, R4 is not a side chain of a naturally occurring α-amino acid, and provided that when n is 1, X is CH2, the ring containing X is saturated, and Z and R5 are H, R3 and R4 are not both methyl; or,
(ee) R3 is hydrogen, and R4 and R5 together with the atoms to which they are attached form a 4 to 8 membered heterocyclic ring of 3 to 7 carbons and 1 nitrogen,
wherein the heterocyclic ring carbon atoms other than the carbon connected to N and R4 have the formula —(CR22R23)m— wherein m is 2 to 6, and R22 and R23 are independently hydrogen, hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, halo, amino, substituted amino, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, alkylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, alkoxycarbonyl, aryloxycarbonyl, or alkylaminocarbonylamino; and, optionally the heterocyclic ring has an aryl, heteroaryl or a 3 to 7 membered cycloalkyl ring fused thereto, provided that when n is 1, X is CH2, the ring containing X is saturated, and Z and R3 are H, then R4 and R5 together are not —(CH2)2— or —(CH2)3—.

2. A linear alkyl pyrrolidine compound of formula I according to claim 1 wherein CRi Rii is absent, R3, R4 and R5 are as given in clauses (cc), (dd) and (ee), and the linear alkyl pyrrolidine compound has formula II:

3. A linear beta pyrrolidine compound of formula I according to claim 1 wherein CRi Rii is present, R3, R4 and R5 are as given in clauses (aa) and (bb), and the linear beta pyrrolidine compound has formula III:

Patent History
Publication number: 20070185061
Type: Application
Filed: Nov 6, 2006
Publication Date: Aug 9, 2007
Inventors: David Campbell (San Diego, CA), David Winn (San Diego, CA), Juan Betancort (San Diego, CA), Kevin Shreder (San Diego, CA), Yi Hu (San Diego, CA), Bei Li (San Diego, CA), Melissa Wong (San Diego, CA), Lifu Ma (Melville, NY), William Ripka (San Diego, CA), Min Wu (Sunnyvale, CA)
Application Number: 11/556,944
Classifications
Current U.S. Class: 514/64.000; 548/110.000; 548/405.000
International Classification: A61K 31/69 (20060101); C07F 5/02 (20060101);