JP2003535034A - Dipeptidyl peptidase IV inhibitors and methods for producing and using dipeptidyl peptidase IV inhibitors - Google Patents

Abstract

  (57) [Summary] The present invention provides inhibitors of dipeptidyl peptidase IV based on or comprising proline or similar residues. This inhibitor is useful for the treatment of many diseases, including diseases of the central nervous system and prostate. Many inhibitors can be reversible and can cross the blood-brain barrier. Methods of making and using the inhibitors, as well as methods of treatment, are also provided.

Description

Detailed Description of the Invention

This application is filed on November 12, 1999, US Application Serial No. 09/43
No. 9,089 is a continuation-in-part application, which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION The present invention relates to new and improved inhibitors of dipeptidyl peptidase IV (“DPP IV”), as well as new and improved therapeutic methods and related uses.
The DPP IV inhibitors of the present invention are useful for the treatment of a wide range of diseases and other abnormal conditions, including those that impact the central nervous system.

Dipeptidyl peptidase IV is a membrane-bound peptidase involved in the cleavage of N-terminal dipeptides from other types or forms of proteins and peptides. This enzyme is a type II membrane serine peptidase and is additionally selective for removing proline-containing dipeptides from the N-terminus of proteins or peptides. This enzyme contains 767 amino acids and has been found in kidney, epithelial cells, endothelial cells, small intestine, prostate, seminal plasma, and brain.

The physiological role of DPP IV is not completely understood. DPP IV
Has been thought to play a role in the cleavage of many cytokines, growth factors, and neuropeptides. This enzyme is also capable of cleaving neuropeptides such as substance P and neuropeptide Y. DPP IV is involved in cell adhesion
There was also a suggestion that it is related to the cell activation marker CD26.

DPP IV is associated with disease states such as HIV infection, diabetes, arthritis, and certain cancers. For example, the presence of DPP IV is associated with prostate and lung cancer, and DPP IV has also been found in patients with benign prostatic hypertrophy. DP
PIV has also been studied for its role in type II diabetes, because the glucagon-like peptide (GLP-1) can be a substrate for the cleavage of DPP IV, and even some DPPs. This is because the IV inhibitor has been shown to be effective in the animal model of diabetes. In addition, DPP IV
It has been linked to HIV infection by its association with CD26. DPP IV also
It is recognized as the "research front" in the literature on Alzheimer's disease. Shvaloff et al., DIALOG FILE No. 05335738/5.

Inhibition of DPP IV is a protein with neuroprotective properties, TGF-β
Shows an increase in the release of. DPP IV inhibition itself, however, is not involved in the neuroprotective context.

Inhibition of DPP IV has been studied in the treatment of autoimmune diseases such as diabetes, arthritis, and multiple sclerosis (a demyelinating disease of peripheral nerves). PCT release WO9
See 7/40832 and WO98 / 19998. In addition, PCT release W
O94 / 03055 discusses increasing production of hematopoietic cells with DPP IV inhibitors. PCT Publication WO 95/11689 discloses the use of DPP IV inhibitors to block the entry of HIV into cells. US Patent No. 5,
543,396 discloses the use of inhibitors, certain proline phosphate derivatives, for the treatment of tumor metastases. PCT Publication WO 95/34538 describes the use of certain serine protease inhibitors (eg, certain DPP IV and PEP inhibitors) to treat peripheral nervous / autoimmune diseases similar to multiple sclerosis. To mention.

DPP IV inhibitors based on molecules with analogs of proline have been investigated in the art. For example, PCT Publication WO 95/11689 discloses α-aminoboric acid analogs of proline. PCT Publication WO98 / 19998 is DPP I
N-substituted 2-cyanopyrrolidines are disclosed as V inhibitors. PCT release WO9
5/34538 also discloses a number of proline containing compounds. Alexander
(Alexander) et al., BIOSIS NO. 199900218969 discusses studies on prolylpyrrolidine phosphonates, which are considered irreversible DPP IV inhibitors. U.S. Patent Nos. 6,011,155; 6,110,949;
And 6,124,305, for diabetes and "dipeptidyl peptidase-V.
Disclose a number of N-substituted cyanopyrrolidines and cyanothiazolidines for inhibiting DPP IV for the treatment of "conditions brought about by the inhibition of."

[0009] The field, however, lacks an understanding of the utility of DPP IV for the treatment of disease states, injuries, and other abnormal conditions including the central nervous system and other parts of the body, eg, prostate. In the treatment of. Therefore, there is a need for safe and effective compositions and methodologies for the treatment of disease states, injuries, and other abnormal conditions including the central nervous system and other parts of the body by inhibiting DPP IV. Exists. These requirements have not been resolved until the development of the present invention.

SUMMARY OF THE INVENTION In view of the need for techniques to provide novel therapeutic products, methodologies, and uses, it is an object of the present invention to provide inhibitors of dipeptidyl peptidases.

In achieving this and other objects, in accordance with one aspect of the invention, there are provided inhibitors of dipeptidyl peptidase IV. Inhibitors according to the present invention include proline mimetics and include about 1 μM or less, preferably 100 nM.
It can have an IC ₅₀ of less than 700, and even a molecular weight of less than 700, preferably less than about 500. Preferably the inhibitor is reversible. Where the inhibitor, including the central nervous system, would be used to treat a disease, the inhibitor is preferably sufficiently neutral or non-polar and therefore by passive diffusion. Can cross the blood-brain barrier. In many cases, inhibitors that cannot pass by passive diffusion will instead pass by active transport. Of course, when treating the central nervous system, a dosing approach may also be used to avoid adverse interference from the blood-brain barrier. Inhibitors for use according to the invention are c-KP
G and, as shown below, Core Structures (I), (II), (
III) or an inhibitor represented by (IV).

According to another aspect of the invention, dipeptidyl peptidase
A reversible inhibitor of IV is provided, wherein the inhibitor is preferably reversible, and preferably central structure (I), central structure (
II), a core structure (III), and a core structure (IV). These core structures have functional groups and substituents such as X
, X ₁ , A, Z, and R, where X (if present) is
CR2R3, O, S, or NR4; X ₁ (if present) is CR2R3
, O, S, or NR4, provided that both X and X ₁ cannot be heteroatoms; A is H, COOH, or a carboxylic acid isostere.
rs), for example, CN, SO ₃ H, CONOH, PO ₃ R5R6, SO ₂ NHR7
, Tetrazole, amide, ester, and acid anhydride; Z (when present) is O or S; and many of the above R groups present are H , C ₁ -C ₉ branched or straight chain alkyl, C ₂ -C ₉ branched or straight chain alkenyl, C ₃ -C ₈ cycloalkyl, C ₅ -C ₇ cycloalkenyl, aryl, heteroaryl, and amino. independently selected from the group of functional groups, wherein any of the above functional group, one or more C ₁ -C ₉ straight or branched chain alkyl, aryl, heteroaryl, amino, halogen, carbonyl, C ₁ ~ C ₉ alkoxy, C ₂ -C ₉ alkenyloxy, phenoxy, benzyloxy, C ₃ -C ₈ cycloalkyl, cyano, amido, thiol, can be substituted by trifluoromethyl, or hydroxy, Here, each of R and R1 can be the same or different; all substituents contemplated herein are permissible for many conditions, one or any combination thereof. However, the condition is that, for example, when one group is included in a defined position, another group at the same or different position can be excluded; and according to yet another aspect of the present invention, DP patients with diseases involving the central nervous system
Methods of treating with inhibitors of P IV are provided. Preferably, the inhibitor for use in the method should preferably be reversible, and, preferably,
A sufficient amount to treat the disease should be able to cross the blood-brain barrier. A compound according to the invention may be (concurrently) or sequentially (s)
can be administered sequentially). In addition, different compounds according to the invention (eg different compounds of one of the above core structure groups, or compounds of two or more of the above core structure groups) can be administered simultaneously or sequentially. The use of the compounds disclosed herein is (1) for the treatment of diseases of the central nervous system, and (2)
Provided for manufacturing compositions, formulations and medicaments for treating disorders of the central nervous system.

According to yet another aspect of the present invention, there is provided a method of treating a patient having a disease of the prostate, including prostate abnormalities such as prostate cancer and nerve recovery after prostatectomy.
Preferably, the inhibitor for use in the method should be reversible and capable of spreading and acting on the prostate. The compounds of the invention can be administered concurrently with other compounds or sequentially. In addition, different compounds of the invention (eg, different compounds of one of the above core structure groups, or compounds of two or more of the above core structure groups) can be administered simultaneously or sequentially. The use of the compounds disclosed herein is (1) for the treatment of prostate disease, and (
2) Provided for the manufacture of compositions, formulations and medicaments for treating prostate disorders.

The above and other aspects of the invention will be apparent to those skilled in the art in view of the disclosure contained herein.

Detailed Description of the Preferred Embodiments The present invention provides inhibitors of DPP IV that are useful for treating a number of disorders, which disorders include, among others, disorders of the central nervous system. Preferably D
Inhibitors of PP IV are pyrrolidine-based compounds, and more preferably constitute or include proline or proline mimetics. The compounds of the invention preferably have sufficient stability, potency, selectivity, solubility, and availability, for example, diseases, injuries, and other abnormalities to the central nervous system, peripheral nerves, and prostate. Safe and effective in the treatment of severe conditions or trauma.

As used in connection with the present invention, there are many grammatical forms of “trea”.
The term “t)” refers to a disease state, disease progression, injury, trauma, ischemia, vector that causes disease (eg, bacteria, protozoa, parasites, fungi, viruses, viroids, and / or prions). , To prevent the deleterious effects of surgical procedures or other abnormal or detrimental conditions, all of which are collectively referred to as "disorders," as would be understood by one of skill in the art. preventing), treating (c
uring, attenuating, alleviating, minimizing, suppressing, improving (ameliorat)
ing), or halting. A “therapeutically effective amount” of an inhibitor according to the present invention is an amount that can achieve an effective treatment, and such amount is determined in the context of this disclosure. be able to.

As explained above, DPP IV exhibits selectivity leading to the removal of proline-containing dipeptides from the N-terminus of proteins or peptides. Therefore, proline has a structure that is easily recognized and acted upon by the active site of DPP IV. Proline is unique among the 20 natural amino acids and contains in it a cyclic secondary amino group, which results in interruptions in the α-helical structure in proteins or peptides. Will cause you to make.

Preferably, the inhibitors of DPP IV according to the present invention may comprise or comprise proline or proline-like residues, which are often referred to as “proline-like residues”. It is described as "proline mimetics". A mimicry of proline is a structure that is sufficiently similar to proline, and its charge, polarity, shape, and size are, for example, many of the molecular interactions involving proline. Enough replication of proline to participate in. A molecule or other compound containing a proline residue may itself be considered a mimicry of proline. Thus, a molecule that constitutes or contains proline or a mimicry of proline can interact with the natural interaction partner of proline, such as DPP IV.
Preferably, an inhibitor of DPP IV has the same or greater affinity for DPP IV as a natural substrate of DPP IV, eg, a protein containing a proline residue at its N-terminus. Preferably, the inhibitors will have the same or greater affinity and will allow the inhibitors to more effectively compete for the active site of DPP IV. Inhibitors with lesser affinity, however, are still within the scope of the invention, and in addition effective competition, and thus inhibition, can be ensured through the consideration.

According to one aspect of the invention, inhibitors of DPP IV are used to treat a disease of the prostate, including but not limited to prostate cancer and nerve recovery after prostatectomy. Not done. For example, erection and excretion disorders are very common clinical conditions that result from diseases, injuries, and trauma associated with pelvic surgery, including complications. Peripheral nerve injury during major pelvic surgery is believed to cause complications such as erectile dysfunction and urinary incontinence. These complications can be attributed to the nerves that innervate the area during surgery (eg,
It may be caused by trauma or injury to the carvernous nerve. Reasonable administration of an inhibitor of DPP IV before, during, and after surgery may be effective in blocking the nerve degeneration caused by pelvic surgery.

The inhibitors of the present invention can be administered in methods used in conjunction with other therapeutics for prostate treatment, and may also be combined with other products or methodologies for treating the prostate. it can. A therapeutically effective amount of an inhibitor will depend on its potential and ability to invade or become available at the site of treatment, in this case the prostate and / or the area surrounding it, at that site. Considerations for determining the proper dosage level are available to those of skill in the art. See Example 6 below.

According to another aspect of the invention, inhibitors of DPP IV can be used to treat diseases of the central nervous system (CNS) and peripheral nerves. For example, DPP according to the present invention
Inhibitors of IV include CNS disorders such as strokes, tumors, ischemia (
ischemia), Parkinson's disease, memory loss,
Hearing loss, vision loss, migraines, brain injury, spinal cord injury, Alzheimer's disease
mer's disease), amyotrophic lateral sclerosis, which has a component of the CNS. in addition,
Inhibitors of DPP IV can be used to treat diseases with more peripheral properties, including multiple sclerosis and diabetic neuropathy.

When treating the CNS, one encounters a biological phenomenon known as the “blood brain barrier”.
This blood-brain barrier does not allow many compounds in the circulation to cross the brain. The brain is a complex biological structure that is susceptible to many toxins. In addition, the brain is composed primarily of nerves and related tissues, which lacks the natural regenerative capacity of other organs and tissues. For example, skin has a wide range of regenerating and healing abilities, and
As such, they can resist encounters with toxins and other physical attacks, which can be expected to be encountered in daily life. The brain itself, on the other hand, is highly susceptible to toxins, and therefore the blood-brain barrier is thought to have been an evolutionary development to protect the integrity of the brain. The blood-brain barrier, however, can also prevent the ingress of beneficial compounds, such as pharmaceuticals needed to treat diseases, injuries, or other abnormal conditions. Therefore, the blood-brain barrier can be a complicating factor in developing therapeutics for the CNS.

Compounds, eg molecules, cross the blood-brain barrier by two basic pathways called “passive diffusion” and “active transport”. Designing compounds for crossing the blood-brain barrier by passive diffusion is somewhat easier than designing compounds for crossing by active transport. An evaluation method for assessing the ability of a compound to cross the blood-brain barrier is described by Boer et al., DRUG TRANSPORT ACROSS THE BLOOD-BRAIN BARRIE.
R (Harwood Academic Publishers).

Guidelines exist for creating compounds that cross the blood-brain barrier by passive diffusion. Typically, compounds that cross the blood-brain barrier by passive diffusion are:
It should have a log P of about 1 to about 4. In connection with this concept, log D
, Which takes into account the charge of the compound. Typically, polar and charged compounds are not very easy to cross the blood brain barrier by passive diffusion. Therefore, a log D greater than about −2 is preferred. logP and lo
The concept of GD is Waterbeemed, STRUCTURAL-PROPERTY CORRELATIONS IN DRUG RE
Discussed in SERCH (Academic Press).

To further facilitate passive diffusion, the compound preferably has a molecular weight of about 700 or less, preferably about 500 or less. Thus, a compound for crossing the blood-brain barrier by passive diffusion should be "sufficiently neutral or non-polar" because of the size it is capable of crossing the blood-brain barrier in a therapeutically effective amount. Is.

Compounds that have a larger and / or higher charge and are also polar
Within the scope of the invention. Typically, these compounds do not cross the blood-brain barrier by passive diffusion, but rather they cross this barrier by active transport.
There are guidelines for developing compounds that will be traversed by active transport.
In addition, mode of administration, delivery vehicle, and other formulation considerations can help the compounds according to the invention cross the blood-brain barrier. See, for example, US Pat. No. 5,874,449.

Apart from the compound's effectiveness in crossing the blood-brain barrier, another important consideration is the ability of this compound as an inhibitor. For example, potent inhibitors may have less efficiency in crossing the blood-brain barrier, but nevertheless they may be effective due to their high potency. Conversely, less potent inhibitors would require greater efficiency in crossing the blood brain barrier in order to have beneficial effects. Therefore, a therapeutically effective amount for treating CNS disorders will depend on the potency of this inhibitor and its efficiency to cross the blood-brain barrier or the route and method of administration used to bypass the blood-brain barrier. Dependent.

With respect to efficacy, DPP IV inhibitors preferably have an IC ₅₀ value (representing an inhibitory concentration at which 50% of DPP IV is inhibited) of less than about 1 μM, more preferably less than 100 nM. Of course, DPP IV inhibitors will have greater IC ₅₀ values as long as their efficiency at crossing the blood-brain barrier is sufficient to treat a disease, injury, or other abnormal condition. You can

The DPP IV inhibitor according to the present invention is preferably a reversible inhibitor. That is, the DPP IV inhibitor should be able to interact with the inhibitor in a manner that would denature or inactivate the DPP IV enzyme without permanently binding the inhibitor. The need for reversibility is that DPP IV
It is based on the fact that it is a naturally occurring enzyme with normal physiological function. Irreversible inhibitors are able to effectively eliminate the function of this enzyme, thus leading to interruption of normal physiological processes. The present invention has particular context, for example,
In the treatment of ischemic events, inhibition of DPP IV is utilized during a limited period of time, such as during and after reperfusion in the area of ischemia. A reversible inhibitor will allow the inhibited DPP IV molecule to restore normal function once the need for inhibition leaves.

Routes of Administration and Formulations For treating the CNS, the compounds according to the invention can be administered by a number of systemic and CNS-targeted routes. For example, intra-arterial, intravenous, indoor
Intraventricular, intracavitary, and intracranial routes of administration can be used. Typical injection formats can be by bolus, regular injection, and / or continuous infusion methods.

Depending on the circumstances, the following routes can be used for the compounds according to the invention, which are parenteral, oral, nasal, inhalation spray, cheek, topical, transdermal, rectal, vaginal, implantation. Included via an implanted reservoir, or other routes available to those of skill in the art. The term parenteral as used herein is subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intravenoustricular, intrasternal (int).
rasternal, intracranial, intraosseous injection or infusion techniques.

To be most effective as a therapeutic for central nervous system disorders,
The compounds according to the invention preferably penetrate the blood-brain barrier when administered peripherally. Compounds that are unable to sufficiently cross the blood-brain barrier can be effectively administered by the intraventricular route. It is noted that during the active phase of certain CNS disorders, a blood-brain lineage is known to be generated, which will allow entry of the compounds of the invention into the central nervous system. It is also important to keep. Moreover, there are several other techniques that physically break through or bypass the blood-brain barrier to deliver therapeutic agents. Examples of such techniques include intrathecal injection, surgical implantation, and osmotic tech.
niques) are included.

Invasive techniques are often used, but especially direct administration to injured nerve tissue. One or more of the above may be used in accordance with the present invention.

One embodiment for the administration of the compounds of the present invention is by intrathecal injection, ie directly into the cerebrospinal fluid by puncturing the membrane surrounding the central nervous system. Yes, usually by lumbar puncture. Direct continuous administration into the cerebrospinal fluid can be achieved through the use of surgically implanted infusion pumps.

Another embodiment for the administration of the compounds of the invention is by direct injection into the lumbar cranial nerve fluid (intrathecal) or by intravenous injection.

The compounds according to the invention can be combined with pharmaceutically acceptable carriers and diluents and can also be used in the methods and uses according to the invention. Formulation will depend on the condition of the disease being treated and the route of administration. See, for example, incorporated US Pat. No. 5,874,449. Pharmaceutically acceptable carriers include aqueous solutions, non-toxic diluents, salts, preservatives, buffers such as phosphate buffers, and the like, which can be found in the United States Pharmacopoeia and Federal Formulations. (UNITED STATES PHARMACPEIA AND NATIONAL FORMULARY) (USP 24-NF 19);
REMINGTON'S PHARMACEUTICAL SCIENCES; HANDBOOK ON PHARMACEUTICAL EXCIPIEN
TS (2nd edition, edited by Wada and Weller, 1994), each of which is incorporated herein by reference. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, saline solutions, parenteral vehicles such as sodium chloride and Ringer's dextrose. Intravenous carriers include fluid and nutrient replenishers. Preservatives include anti-bacteria, antioxidants, chelating agents, and inert gases. pH and solidified (bin
The exact concentrations of the many components of the ding composition will be adjusted according to conventional techniques in the art. See THE PHARMACOLOGICAL BASIS FOR THE RAPEUTICS (9th edition) of GOODMAN and GILMAN, the contents of which are incorporated herein by reference.

A typical approach involves the compounds to be administered in the form of a sterile injectable preparation, for example as a sterile injectable aqueous or oleaginous suspension. The sterile injectable preparation may also be an injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. it can. Among the acceptable vehicles and solutions that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are generally used as a solvent or suspending medium. For this purpose any fresh non-volatile oil can be used, for example synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, olive oil and castor oil, especially in their polyoxyethylated forms, are useful in the preparation of injectable pharmaceuticals. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.

In addition, the compounds may also be administered orally in the form of capsules, tablets, aqueous suspensions or solutions; tablets may be carriers such as lactose and corn starch, and / or lubricants such as stearic acid. It can include magnesium. Capsules can contain a diluent including lactose and dried corn starch. Aqueous suspensions may include emulsifying agents and suspending agents with the active ingredient. The oral dosage form may further comprise sweeteners and / or flavors and / or colorants.

The compounds can also be administered rectally in the form of suppositories. These formulations may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature, thus it is rectal It will melt in and release the drug. Such excipients include cocoa butter, beeswax, and polyethylene glycols.

Furthermore, the compounds may also be administered topically, especially when the condition for treatment involves areas or organs readily accessible by topical application. , Skin, or lower intestinal tract neurological disorders.

For topical application to the eye or ophthalmic use, the compounds are isotonic and p
Preservatives, which can be formulated as finely divided suspensions in H-regulated sterile saline, and also preferably as isotonic, pH-regulated sterile saline solutions, For example, either with or without benzalkonium chloride. Alternatively, the compound can be incorporated into an ointment such as petrolatum.

For topical application to the skin, the compound can be incorporated into a suitable ointment, which may be, for example, the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol. , A polyoxyethylene polyoxypropylene compound, an emulsified beeswax, and a compound suspended or dissolved in a mixture with one or more of water. Alternatively, the compounds can be incorporated into suitable lotions or creams, which are, for example, the following: mineral oils.
oil), sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and suspended or dissolved in a mixture of water. Contains active compounds.

Dosing The compounds of the invention may be administered in a single dose, in multiple discrete doses or by continuous infusion. The compounds are preferably small, easily diffused and quite stable, so that they can be well suited for continuous injection.

Dosage levels on the order of about 0.1 mg to about 10,000 mg of active ingredient are useful in treating the above conditions, with preferred levels of about 0.1 mg to about 1.0.
It is 00 mg. The particular dosage level, and therefore the therapeutically effective amount for any particular patient, will vary depending on many factors, which will depend on the activity of the particular compound used. , And its bioavailability where the drug acts; age, weight, general health, sex, and patient's diet; time of administration; rate of excretion; drug combination; specific illness being treated. And the form of administration. Typically, the in vitro dosage effect results provide useful guidance on the proper dosages for administration to a patient. Studies in animal models are also helpful. Considerations for determining appropriate dosage levels are available to those of skill in the art. See Example 5 below.

Certain compounds may be administered in a vacuum dried form. In this case, 1 to 100 mg of the compound of the invention is added in a separate vial to the carrier or buffer,
It can be lyophilized, for example with mannitol and sodium phosphate. The compound can be reconstituted with bacteriostatic water in its vial prior to administration.

In the treatment of CNS disorders resulting from systemic ischemia, for example, the compounds of the invention are preferably administered orally, rectally, parenterally or topically at least 1 daily.
~ 6 doses can be administered, followed by a higher concentration of the initial bolus dose.

Dosing Regimen and Timing For the compounds, methods, and uses of this invention, all regimens that control the timing and sequence of drug delivery are used as needed to achieve treatment and Can be repeated. Such regimens may include co-administration of pretreatment and / or additional therapeutic agents.

In order to maximize the protection of nerve tissue from nerve injury, the compounds should be administered to the affected cells as soon as possible. In situations where nerve injury is expected, the compound should be administered prior to the expected nerve injury. Such situations with increased likelihood of nerve injury include surgery (eg, carotid endarterectomy, cardiac, vascular, aortic, orthopedic surgery); endovascular proced
ure), for example, catheterization of an artery (eg, carotid, spinal, aortic,
Cardiac, renal, spinal, Adamkiewicz catheterization; injection of embolic agents; coils or balloons for hemostasis; blockage of blood vessels for treatment of brain injury; and medical Producing a predisposition to the condition includes, for example, progressively stronger crescendo transient ischemic attacks, embolic and continuous strokes. Where pretreatment for stroke or ischemia is not possible or practical, it is important to bring the compound to the affected cells during or as soon as possible thereafter. During the time between strokes, diagnostic and therapeutic measures should be minimized in order to rescue the cells from further injury or death.

The effect of cerebral ischemia, both in animal models of stroke and in humans, is
It becomes immediately apparent on the metabolism of the brain, in units of time measured in minutes or hours. Any form of possible neuroprotective treatment should therefore be given by the fastest and most effective route, which in practice usually implies the intravenous route. The optimal duration and route of administration for treatment will depend on the individual pharmacokinetic properties of the neuroprotective compound, aspects of the drug's adverse effects, and the nature of the trauma that caused the stroke. Injury of stimulant toxic substances following an attack is at least 4 in rodents.
It appears over time, perhaps 48 hours in humans. Dyker et al., Stroke 2
9: 535-42 (1998). Therefore, it would be preferable to provide neuroprotection during this dangerous time period. Ideally, any compound for the treatment of seizures should cross the blood-brain barrier well, and should also achieve adequate therapeutic levels in the brain and cerebrospinal fluid. is there. Not progressing,
For patients with prostate cancer who have also not metastasized, the compounds of the invention may be administered, which are (i) prior to surgery or radiation therapy to reduce the risk of metastasis; (ii) during surgery. Or in combination with radiation treatment; and / or (iii) after radiation treatment to reduce the risk of surgery or recurrence and to suppress the growth of all residual tumor cells.

For patients with advanced or metastatic prostate cancer, the compounds of the invention may be administered which result in tumor cell growth both in the untreated primary tumor and in existing metastatic lesions. As an alternative to continuous replenishment or excision to a homonal resection to slow it down.

The compounds, methods, and uses of the invention are particularly useful where shed cells cannot be removed by surgical intervention. After recovery from surgery, the compounds, methods, and uses of the invention will be effective in reducing the chance of tumor recurrence produced by such spilling cells.

Combination with Other Therapies The compounds, methods and uses of this invention are also to provide a combined formulation for simultaneous, separate or sequential use, It contains other biologically active drugs.

Such biologically active drugs are further compounds of the invention; steroids such as hydrocortisomers such as methylprednisolone (me).
thylprednisolone); anti-inflammatory or anti-immune drug such as methotrexate
xate), azathioprine, cyclophosphamide
mide) or cyclosporin A; interferon-β; antibodies, such as anti-CD-4 antibodies; drugs that can reduce the risk of secondary ischemic events,
For example, ticlopidine; chemotherapeutic composition (chemotherapeutic co
mpositions); immunotherapeutic compositions; morphine for the treatment of pain; or mixtures thereof.

The compounds according to the present invention will contain many substituents available to those skilled in the art and will be used in accordance with the teachings contained herein. For example, a core structure that builds or includes a proline mimicry can include many functional groups as taught herein. In addition, the invention includes the isosteres of the compound or functional groups included herein. Functional groups and isostere principles (Guid
ing principle) and examples are Smith et al., INTRODUCTION TO THE PRINCIPLES OF DR
It is shown in UG DESIGN (John Wright & Sons, Ltd.) and is incorporated herein by reference.

The compounds used according to the invention are preferably in their core structure
Contains residues that are similar to or similar to proline. That is, these compounds are or include proline mimetics. One such compound that can be used in accordance with the present invention comprises a proline mimetic and has the following structure:

[0056]

[Chemical 11]

[0057] Have.

This compound, referred to as “c-KPG”, is of organotypic type.
Spinal motoneurons and threohydroxyaspartate (threohydorxyaspa
rtate) (“THA”) was tested and is an inhibitor of the glutamate reuptake receptor. c-KP
The synthetic scheme for G is disclosed in Nguyen et al., J. Med. Chem. 41: 2101-10 (1998).

As shown in FIG. 1, exposing THA alone to neurons results in 55-60% death of the neurons. Exposing neurons to THA in combination with 10 μM c-KPG (an inhibitor of DPP IV) caused c-KPG to be more than 50% of the neurons that would have been killed if exposed to THA alone. Saved a lot. This result is very significant (p = 0.004).

The present invention includes other core structures as well. The core structure is DPP IV
An inhibitor, which further constitutes or comprises a mimicry of proline, is described below. Representative core structures are depicted graphically, and functional / substituent groups are described in the text. All substituents envisioned herein are free under many conditions, either singly or in any combination, provided that one group is contained at one defined position. , Another group at the same or different position can be excluded. For example, the core structure (I) is:

[0061]

[Chemical 12]

Which may be modified as described below, but subject to the following freely selectable conditions specified by the number, which may be employed alone or in any combination. Can: X is CR2R3, O, S, or NR4; optional condition 1 is that when X is S, A cannot be CN; optional condition 2 is that X is CH ₂ . And if R is H, then A cannot be C; optional condition 3 is: if X is S, then R 1 cannot be an amino-substituted alkyl; , X cannot be COOH when X is CH ₂ ; optional condition 5 is that X is S
Or if X and X1 are both CH ₂ , Z is O, A is CN, and R1 is H, then R is C1-C9 straight or branched chain alkyl X is ₁ or CR2CR3, O, S, or NR4 with the proviso that: X and X1 cannot both be heteroatoms; optional condition 7 is that X and X1 are both CH ₂ and Z is O;
And when R1 is NH _2, when A is COOH, R is not 1-methyl-propyl, and, when A is CN, R is not a cyclopentyl; A is H, COOH, or carboxylic acid Isosteres, eg CN
, SO ₃ H, CONOH, PO ₃ R5R6, SO ₂ NHR7, tetrazole, an amide, an ester, and an acid anhydride, with the proviso that any of the following 8 There is CN, and R1 is NH _2,
And Z is O and R is 1-methylpropyl, both X and X1 are not CH ₂ , X and X1 are not S, X is not O, and Z is O or S. ; R and R1, H, C ₁ -C ₉ branched or straight chain alkyl, C ₂ -C ₉ branched or straight chain alkenyl, C ₃ -C ₈ cycloalkyl, C ₅ -C ₇ cycloalkenyl, aryl, Independently selected from the group of functional groups consisting of heteroaryl and amino, wherein any of the above functional groups is one or more C ₁ -C ₉ straight or branched chain alkyl, aryl, heteroaryl, amino, Substituted with halogen, carbonyl, C ₁ -C ₉ alkoxy, C ₂ -C ₉ alkenyloxy, phenoxy, benzyloxy, C ₃ -C ₈ cycloalkyl, cyano, amide, thiol, trifluoromethyl, or hydroxy. Where each of R and R1 can be the same or different; and R2, R3, R4, R5, R6, and R7, if present, are H, C ₁
To C ₉ branched or straight chain alkyl, C _{2 to} C ₉ branched or straight chain alkenyl, C _{3 to} C ₈ cycloalkyl, C _{5 to} C ₇ cycloalkenyl, aryl, heteroaryl, and amino. Independently selected from the group, where each of these functional groups is 1
The above C _{1 to} C ₉ straight chain or branched chain alkyl, aryl, heteroaryl, amino,
It may be substituted with halogen, carbonyl, C ₁ -C ₉ alkoxy, C ₂ -C ₉ alkenyloxy, phenoxy, benzyloxy, C ₃ -C ₈ cycloalkyl, cyano, amide, thiol, trifluoromethyl, or hydroxy. Yes, here, R2
, R3, R4, R5, R6, and R7, if present, can be the same or different.

Other core structures are provided according to the invention, for example those with ring modifications (formula (II) and formula (III) below):

[0064]

[Chemical 13]

This (II) can be modified as follows: X is CR2R3, O, S, or NR4; A is H, COOH, or carboxylic acid isosteres, For example CN
, SO ₃ H, CONOH, PO ₃ R5R6, SO ₂ NHR7, tetrazole, amide, ester, and acid anhydride; and Z is O or S; R and R1 are , H, C ₁ -C ₉ branched or straight chain alkyl, C ₂ -C ₉ branched or straight chain alkenyl, C ₃ -C ₈ cycloalkyl, C ₅ -C ₇ cycloalkenyl, aryl, heteroaryl, and amino. Independently selected from the group of functional groups consisting of, wherein any of the above functional groups is one or more C _{1 to} C ₉ straight or branched chain alkyl, aryl, heteroaryl, amino, halogen, carbonyl, C ₁ -C ₉ alkoxy, C ₂ -C ₉ alkenyloxy, phenoxy, benzyloxy, C ₃ -C ₈ cycloalkyl, cyano, amido, thiol, trifluoromethyl, or substituted with hydroxy Is it possible, where each of R and R1 is can be the same or different; when and R2, R3, R4, R5, R6, and R7, in which it resides, H, C ₁
To C ₉ branched or straight chain alkyl, C _{2 to} C ₉ branched or straight chain alkenyl, C _{3 to} C ₈ cycloalkyl, C _{5 to} C ₇ cycloalkenyl, aryl, heteroaryl, and amino. Independently selected from the group, where each of these functional groups is 1
The above C _{1 to} C ₉ straight chain or branched chain alkyl, aryl, heteroaryl, amino,
It may be substituted with halogen, carbonyl, C ₁ -C ₉ alkoxy, C ₂ -C ₉ alkenyloxy, phenoxy, benzyloxy, C ₃ -C ₈ cycloalkyl, cyano, amide, thiol, trifluoromethyl, or hydroxy. Yes, here, R2
, R3, R4, R5, R6, and R7, if present, can be the same or different.

[0066]   The core structure (III) has the following:

[0067]

[Chemical 14]

Is represented by and can be modified as follows: A is H, COOH, or a carboxylic acid isosteres, such as CN
, SO ₃ H, CONOH, PO ₃ R5R6, SO ₂ NHR7, tetrazole, an amide, an ester, and an acid anhydride; and Z is O or S; R, R1, R2, and R3, H, C ₁ -C ₉ branched or straight chain alkyl, C ₂ -C ₉ branched or straight chain alkenyl, C ₃ -C ₈ cycloalkyl, C ₅ -C ₇ cycloalkenyl, aryl, Independently selected from the group of functional groups consisting of heteroaryl and amino, where any of these functional groups is also one or more C ₁ -C ₉ straight or branched chain alkyl, aryl, heteroaryl, amino, halogen, carbonyl, C ₁ -C ₉ alkoxy, C ₂ -C ₉ alkenyloxy, phenoxy, benzyloxy, C ₃ -C ₈ cycloalkyl, cyano, amido, thiol, trifluoromethyl, or Droxy, where each of R, R1, R2, and R3 can be the same or different; and R4, R5, R6, and R7, if present, H, C ₁ ~C ₉ branched or straight chain alkyl, C ₂ -C ₉ branched or straight chain alkenyl, C ₃ -C ₈ cycloalkyl, C ₅
To C ₇ cycloalkenyl, aryl, heteroaryl, and amino are independently selected from the group of functional groups, wherein each of these functional groups is one or more C _{1 to} C ₉ straight or branched chain alkyl. , Aryl, heteroaryl, amino, halogen, carbonyl, C ₁ -C ₉ alkoxy, C ₂ -C ₉ alkenyloxy, phenoxy, benzyloxy, C ₃ -C ₈ cycloalkyl, cyano, amide, thiol, trifluoromethyl, Or it can be substituted with hydroxy, where R4, R5, R6,
And each of R7, if present, can be the same or different.

Other compounds in accordance with the invention include amide bond isosteres, such as core structure (IV). The core structure (IV) has the following:

[0070]

[Chemical 15]

Is represented by and can be modified as follows: X is CR2R3, O, S, or NR4; X ₁ is CR2R3, O, S, or NR4, where X is And X1 both
A cannot be a heteroatom; A is H, COOH, or a carboxylic acid isosteres, such as CN
, SO ₃ H, CONOH, PO ₃ R5R6, SO ₂ NHR7, tetrazole, an amide, an ester, and an acid anhydride; and R and R1 are H, C _{1 to} C ₉ min. branched or straight chain alkyl, C ₂ -C ₉ branched or straight chain alkenyl, C ₃ -C ₈ cycloalkyl, C ₅ -C ₇ cycloalkenyl, aryl, heteroaryl, and independently from the group of functional groups consisting of amino chosen here, all of these functional groups may include one or more C ₁ -C ₉ straight or branched chain alkyl, aryl, heteroaryl, amino, halogen, carbonyl, C ₁ -C ₉ alkoxy, C ₂ ~ C ₉ alkenyloxy, phenoxy, benzyloxy, C ₃ -C ₈ cycloalkyl, cyano, amido, thiol, it can be substituted by trifluoromethyl, or hydroxy, this In each of R and R1 is can be the same or different; and R2, R3, R4, R5, R6 and R7, when present, H, C ₁ ~
C ₉ branched or straight chain alkyl, C ₂ -C ₉ branched or straight chain alkenyl, C ₃ -C ₈ cycloalkyl, C ₅ -C ₇ cycloalkenyl, aryl, a group of functional groups consisting of heteroaryl, and amino Independently selected from any of these functional groups, where any one or more of these C _{1 to} C ₉ straight or branched chain alkyl, aryl, heteroaryl, amino, halogen, carbonyl, C _{1 to} C ₉ alkoxy, C ₂ -C ₉ alkenyloxy, phenoxy, benzyloxy, C ₃ -C ₈ cycloalkyl, cyano, amido, thiol,
Can be substituted with trifluoromethyl, or hydroxy, where R2, R
Each of 3, R4, R5, R6, and R7, if present, can be the same or different.

Compounds of this core structure according to the present invention can be administered in the form of esters or salts according to the teachings provided herein. Acceptable formulations, dosages, and dosing regimens can be determined according to the teachings contained herein.

The present invention is further described by the following examples, which are illustrative of the invention and are not intended to limit the invention in any way.

Example 1: Synthesis of compounds according to core structure (I) Compounds according to core structure (I) can be prepared according to a number of approaches. A typical approach is shown below:

[0075]

[Chemical 16]

[0076]   Alternative methods include:

[0077]

[Chemical 17]

Substituents can be placed on the ring by modification of the starting materials, as shown below:

[0079]

[Chemical 18]

Compounds containing sulfur at the oxygen position can be prepared according to the following general procedure, shown below:

[0081]

[Chemical 19]

[0082]   Further conversion can be achieved by:

[0083]

[Chemical 20]

[0084]   Other representative compounds are shown below.

Compound 1

[0086]

[Chemical 21]

Compound 2

[0088]

[Chemical formula 22]

Compound 3

[0090]

[Chemical formula 23]

Compound 4

[0092]

[Chemical formula 24]

Compound 5

[0094]

[Chemical 25]

Compound 6

[0096]

[Chemical formula 26]

Compound 7

[0098]

[Chemical 27]

Compound 8

[0100]

[Chemical 28]

Compound 9

[0102]

[Chemical 29]

Compound 10

[0104]

[Chemical 30]

Compound 11

[0106]

[Chemical 31]

Compound 12

[0108]

[Chemical 32]

Compound 13

[0110]

[Chemical 33]

Compound 14

[0112]

[Chemical 34]

Compound 15

[0114]

[Chemical 35]

Compound 16

[0116]

[Chemical 36]

Compound 17

[0118]

[Chemical 37]

Compound 18

[0120]

[Chemical 38]

Other compounds for use according to the invention include: Compound 19: 1- [2-[(5-chloropyridin-2-yl) amino] ethylamino] acetyl-2-cyano- (S ) -Pyrrolidine dihydrochloride; Compound 20: 1- [2-[(5-trifluoromethylpyridin-2-yl) amino] ethylamino] acetyl-2-cyano- (S) -pyrrolidine; Compound 21: 1- [2-[(5-cyanopyridin-2-yl) amino] ethylamino] acetyl-2-cyano- (S) -pyrrolidine dihydrochloride;
Compound 22: 1- [2-[(pyrimidin-2-yl) amino] ethylamino]
Acetyl-2-cyano- (S) -pyrrolidine; Compound 23: 1-[(1-hydroxymethylcyclopent-1-yl) amino] acetyl-2-cyano- (S) -pyrrolidine; Compound 24: 1- [ 2-[(pyridin-2-yl) amino] ethylamino] acetyl-2-cyano- (S) -pyrrolidine; Compound 25: 1- [2-[(4-chloropyrimidin-2-yl) amino] ethylamino ] Acetyl-2-cyano- (S) -pyrrolidine; Compound 26: 1- [2-[(3-chloropyridin-2-yl) amino] ethylamino] acetyl-2-cyano- (S) -pyrrolidine; Compound 27: 1- [2-[(4-trifluoromethylpyrimidin-2-yl)
Amino] ethylamino] acetyl-2-cyano- (S) -pyrrolidine; Compound 28: 1-[(2-chlorophenyl) ethylamino] acetyl-2-cyano- (S) -pyrrolidine; Compound 29: 1-[( 3,3-Diphenyl) propylamino] acetyl-2-
Cyano- (S) -pyrrolidine; Compound 30: 1- [2-[(5-nitropyridin-2-yl) amino] ethylamino] acetyl-2-cyano- (S) -pyrrolidine; Compound 31: 11- [ 2-[(3-chloro-5-trifluoromethylpyridin-2-yl) amino] ethylamino] acetyl-2-cyano- (S) -pyrrolidine; Compound 32: 11- [2-[(3-trifluoro Methylpyridin-2-yl)
Amino] ethylamino] acetyl-2-cyano- (S) -pyrrolidine; Compound 33: 11- [2-[(3,5-dichloropyridin-2-yl) amino] ethylamino] acetyl-2-cyano- ( S) -Pyrrolidine; Compound 34: 11-[(Cyclopent-1-yl) amino-acetyl-2-cyano- (S) -pyrrolidine; Compound 35: 11- [2-[(2-bromo-4,5- Dimethoxyphenyl) ethylamino] acetyl-2-cyano- (S) -pyrrolidine; Compound 36: 11-[(3- (isopropoxy) propylamino] acetyl-
2-Cyano- (S) -pyrrolidine monohydrochloride; Compound 37: 11-[(2-hydroxy-1,1-dimethylethylamino)]
Acetyl-2-cyano- (S) -pyrrolidine monohydrochloride; Compound 38: 11- [3- (2-oxo-pyrrolidin-1-yl) propylamino] acetyl-2-cyano- (S) -pyrrolidine monohydro Chloride;
Compound 39: 3-[(cyclohexyl) amino] acetyl-4-cyano-R-
Thiazolidine monohydrochloride; Compound 40: 3-[(3-isopropoxypropyl) amino] acetyl-4-
Cyano- (R) -thiazolidine monohydrochloride; Compound 41: 3-[(isopropyl) amino] acetyl-4-cyano- (R)
-Thiazolidine monohydrochloride; compound 42

[0122]

[Chemical Formula 39]

Compound 43

[0124]

[Chemical 40]

Compound 44

[0126]

[Chemical 41]

Compound 45

[0128]

[Chemical 42]

Compound 46

[0130]

[Chemical 43]

Compound 47

[0132]

[Chemical 44]

Compound 48

[0134]

[Chemical formula 45]

Compound 49

[0136]

[Chemical formula 46]

Compound 50

[0138]

[Chemical 47]

Compound 51

[0140]

[Chemical 48]

Compound 52

[0142]

[Chemical 49]

Compound 53

[0144]

[Chemical 50]

Compound 54

[0146]

[Chemical 51]

Compound 55

[0148]

[Chemical 52]

Compound 56

[0150]

[Chemical 53]

Compound 57

[0152]

[Chemical 54]

Compound 58

[0154]

[Chemical 55]

Compound 59

[0156]

[Chemical 56]

Compound 60

[0158]

[Chemical 57]

Compound 61

[0160]

[Chemical 58]

Compound 62

[0162]

[Chemical 59]

Compound 63

[0164]

[Chemical 60]

Compound 64

[0166]

[Chemical formula 61]

Compound 65

[0168]

[Chemical formula 62]

Compound 66

[0170]

[Chemical formula 63]

Compound 67

[0172]

[Chemical 64]

Compound 68

[0174]

[Chemical 65]

Compound 69

[0176]

[Chemical formula 66]

Compound 70

[0178]

[Chemical formula 67]

Compound 71

[0180]

[Chemical 68]

Compound 72

[0182]

[Chemical 69]

Compound 73

[0184]

[Chemical 70]

Compound 74

[0186]

[Chemical 71]

Compound 75

[0188]

[Chemical 72]

Compound 76

[0190]

[Chemical formula 73]

Compound 77

[0192]

[Chemical 74]

Compound 78

[0194]

[Chemical 75]

Compound 79

[0196]

[Chemical 76]

Compound 80

[0198]

[Chemical 77]

Compound 81

[0200]

[Chemical 78]

Compound 82

[0202]

[Chemical 79]

Compound 83

[0204]

[Chemical 80]

Compound 84

[0206]

[Chemical 81]

Compound 85

[0208]

[Chemical formula 82]

Compound 86

[0210]

[Chemical 83]

Compound 87

[0212]

[Chemical 84]

Compound 88

[0214]

[Chemical 85]

Compound 89

[0216]

[Chemical 86]

Compound 90

[0218]

[Chemical 87]

Compound 91

[0220]

[Chemical 88]

Compound 92

[0222]

[Chemical 89]

Compound 93

[0224]

[Chemical 90]

Other compounds

[0226]

[Chemical Formula 91]

Embedded image wherein R is NH—R ^I ; R ^I is: C ₁ -C ₁₂ straight or branched chain alkyl; C ₃ -C ₇ cycloalkyl; CH ₂ —CH ₂ —NH— R ^II ; CH ₂ —CH ₂ —R ^III ; CH ₂ —CH ₂ —CHR ^IV —R ^IV ; or CH ₂ —CH ₂ —CH ₂ —R ^V ; R ^II is optionally 1 or 2 positions. Is a pyridine ring substituted with halogen, trifluoromethyl, cyano, or nitro; or a pyrimidine ring optionally substituted in one position with halogen, trifluoromethyl, cyano, or nitro; R ^III Is a phenyl ring optionally substituted at one to three positions with halogen, or C ₁ -C ₃ alkoxy; each R ^IV is independently, optionally at one position, halogen, or C ₁ ~
A phenyl ring substituted with C ₃ alkoxy; and R ^V is a 2-oxopyrrolidine group, or a C ₂ -C ₄ alkoxy group. }

[0228]

[Chemical Formula 92]

Embedded image wherein R is NH—R ^I ; R ^I is: optionally hydroxy, acetyl, C ₁ -C ₃ alkoxy, or C _1-
C ₁ -C ₁₂ straight or branched chain alkyl substituted with C ₃ hydroxyalkyl; optionally substituted with hydroxy, acetyl, C ₁ -C ₃ alkoxy, or C ₁ -C ₃ hydroxyalkyl, C ₃ -C ₁₂ cycloalkyl; adamantyl; indanyl; 1 optionally; bicycloheptyl optionally substituted optionally with 1 to 3 positions by methyl; pyrrolidine substituted by benzyl optionally; optionally piperidyl substituted with benzyl Phenyl substituted on three positions with halogen, methoxy, trifluoromethyl; pyridyl optionally substituted on one to three positions with halogen, trifluoromethyl, nitro; or optionally halogen, trifluoromethyl, been pyrimidyl substituted with nitro; substituted with R ^IV, further optionally in hydroxy Is conversion, a linear or branched alkyl of C ₁ -C _{3; ^{or, (CH 2) 1~3 -NR II}} R III; a, R ^II is hydrogen or methyl; R ^III is Phenyl optionally substituted with CN, or pyridyl optionally substituted with CN; and R ^IV is a group selected from phenyl, naphthyl, cyclohexenyl, pyridyl, pyrimidyl, adamantyl, phenoxy, wherein This group is a phenyl sulfide optionally substituted with ethoxy, methoxy, halogen, phenyl sulfide, or hydroxymethyl in the 1-2 position. } Example 2: Synthesis of compounds according to core structure (II) Compounds according to core structure (II) can be prepared by a number of approaches, provided for core structure (I) above. Includes approaches and methodologies. Suitable starting materials include:

[0230]

[Chemical formula 93]

Other synthetic protocols are also available in the art and are applicable in light of the teachings contained herein. Other representative compounds are described below. Compound 1

[0232]

[Chemical 94]

Compound 2

[0234]

[Chemical 95]

Compound 3

[0236]

[Chemical 96]

Compound 4

[0238]

[Chemical 97]

Compound 5

[0240]

[Chemical 98]

Compound 6

[0242]

[Chemical 99]

Compound 7

[0244]

[Chemical 100]

Compound 8

[0246]

[Chemical 101]

Compound 9

[0248]

[Chemical 102]

Compound 10

[0250]

[Chemical 103]

Compound 11

[0252]

[Chemical 104]

Compound 12

[0254]

[Chemical 105]

Compound 13

[0256]

[Chemical formula 106]

Compound 14

[0258]

[Chemical formula 107]

Example 3: Synthesis of compounds according to core structure (III) Compounds according to core structure (III) can be prepared according to a number of approaches. A typical approach is shown below:

[0260]

[Chemical 108]

Other representative compounds are shown below. Compound 1

[0262]

[Chemical 109]

Compound 2

[0264]

[Chemical 110]

Compound 3

[0266]

[Chemical 111]

Compound 4

[0268]

[Chemical 112]

Compound 5

[0270]

[Chemical 113]

Compound 6

[0272]

[Chemical 114]

Compound 7

[0274]

[Chemical 115]

Compound 8

[0276]

[Chemical formula 116]

Compound 9

[0278]

[Chemical 117]

Compound 10

[0280]

[Chemical 118]

Compound 11

[0282]

[Chemical formula 119]

Compound 12

[0284]

[Chemical 120]

Compound 13

[0286]

[Chemical 121]

Example 4: Synthesis of compounds according to core structure (IV) The methodology for the preparation of compounds according to core structure (IV) is described by Lin et al., Proc. Nat.
'l Acad. Sci. USA 95: 14020-24 (1998). Representative compounds are shown below. Compound 1

[0288]

[Chemical formula 122]

Compound 2

[0290]

[Chemical 123]

Compound 3

[0292]

[Chemical formula 124]

Compound 4

[0294]

[Chemical 125]

Compound 5

[0296]

[Chemical formula 126]

Compound 6

[0298]

[Chemical 127]

Compound 7

[0300]

[Chemical 128]

Compound 8

[0302]

[Chemical formula 129]

Compound 9

[0304]

[Chemical 130]

Compound 10

[0306]

[Chemical 131]

Compound 11

[0308]

[Chemical 132]

Compound 12

[0310]

[Chemical 133]

Compound 13

[0312]

[Chemical 134]

Compound 14

[0314]

[Chemical 135]

Compound 15

[0316]

[Chemical 136]

Compound 16

[0318]

[Chemical 137]

Compound 17

[0320]

[Chemical 138]

Compound 18

[0322]

[Chemical 139]

Compound 19

[0324]

[Chemical 140]

Compound 20

[0326]

[Chemical 141]

Example 5: Procedures for Testing Representative Neuronal Activity Many of the available compounds for assessing neuronal activity of the above compounds, and other compounds designed, manufactured, and used in accordance with the present invention. There are procedures. These assessments can be in vivo or in vitro methods. The approaches described below include evaluations that measure a compound's ability to protect nerve cells from toxic treatment and to elicit nerve cell growth, regeneration, neurite outgrowth and the like.

Immunostaining and Quantitative Evaluation of Neurite Outgrowth Spinal cord and dorsal root ganglion (DRG) cells from adult mice can be isolated by microdissection. Spinal cords were removed from adult mice (15-10 g) with accompanying DRGs. Spinal nerves were excised using microdissecting scissors and further removed of all excess material until DRG alone.
Using sharp microdissection scissors, make a transverse cut in the peripheral nerve, 1-2 mm
Remaining attached, the graft was placed in a Petri dish and covered with plating medium. When all DRGs had been collected, the spinal nerves were trimmed to a length of approximately 1 mm. The graft was then diluted (r
Educed growth factors were embedded in 30 μL of Matrigel and placed in 35 mm culture dishes. Sensory ganglion implants were covered with 2 mls of media. Compound, drug, or control solutions were added from 10X stocks and added to 37
Incubation was at 48 ° C., 5% CO ₂ , 95% humidity for 48 hours. Culture tissue to PB
It was washed twice with S and further fixed with 10% formalin for 30 minutes. The fixed culture tissue was washed twice with PBS and refrigerated in PBS.

The cultured tissue was rotated in Block Buffer (5% horse serum, 5% goat serum, 1% Triton X, PBS pH = 7.4), while rotating.
Placed at a temperature of 4 ° C. overnight. Primary antibody (eg, Beta tubulin, Sigma Chemical Co.) diluted in blocking buffer was added and further incubated overnight at 4 ° C. After washing 5 times with PBS, a second antibody (Alexa 488 goat anti-mouse) diluted in blocking buffer was applied. 4 ° C
Incubate overnight. The plate was washed 5 times with PBS and left overnight at 4 ° C. The cultured tissue was placed on a cover glass, and the total length of neurites from the end of the connected spinal nerve was measured. The length of all neurites was quantified and compared to the length of neurites present in control DRGs treated with carrier.

Evaluation of Neuroprotection Cultured tissue was the lumbar spinal cord of 8 day old (P8) Sprague-Dawley rats.
It was derived from a 325 micron thick slice of spinal cord. Each experiment has 1
It consists of two 6-well plates with 5 slices from 4 different animals per well. The medium was replaced every 3 to 4 days. After 1 week of culturing, the cultured tissues were 200 μM of THA [L (−)-threo-3-hydroxyaspartic acid; Tocris Cookson Inc. , Ballwin, Missouri] + compound (10
μM). The control is an untreated sample with 0.1% DMSO as vehicle. The THA control was TH with 0.1% DMSO as vehicle.
It is a sample processed in A. Two wells were used per condition. New T
One medium exchange was performed with HA and compound. The experiment was stopped 6-8 days following drug treatment (13-15 days total, DIV in vitro) following visual assessment of lesions, but with 4% paraformaldehyde / 0.1 M phosphate buffer. It was due to immobilization for 30 minutes. The flakes were permeabilized with 100% cold methanol for 10 minutes. The slices were transferred to staining wells. The flakes were blocked with 10% HS / TBS. Incubation of primary antibody was performed with SMI in 2% HS / TBS.
-32 antibody 1: 5000 at 4 ° C. overnight. SMI-32 was specific for the non-phosphorylated H neurofilament subunit. Vector Stein ABC Elite Kit (Vecstain ABC E) with rat absorbed anti-mouse secondary antibody
lite Kit) was used with DAB to stain this section. This slice is
The slide glass was placed on the slide, and the cover glass was sealed with a DPX mounting solution.

Quantification of surviving neurons was performed with a Zeiss Axiovert microscope. Neuronal survival was determined by observing the complete neuronal cell body with the processes underlying the central canal of each hemisphere. This is thin film VII, VIII, and IX
Correlates with. Each hemisphere was counted individually. Statistics can be performed using StatView software, based on a minimum of three different experiments per condition, and significance should be determined relative to THA controls. The percent protection can be determined from the average number of surviving neurons by the following formula.

Drug Treatment Conditions-THA Control / (Untreated Control-THA Control) Example 6: Representative Test Procedure for Efficacy of Prostate Treatment Efficacy for Nerve Recovery After Prostatectomy The procedure for testing, administration, and schedule of administration can be performed in connection with the teaching according to Example 5.

There are several lines of cancer cells that can be used to perform in vitro evaluations to evaluate inhibitors of DPP IV in the treatment of prostate cancer. Suitable cell lines are LNCaP, PC3, DU-1 for use in cell proliferation assessment.
45, and TSUPrl.

For example, one cell line can be grown in conventional media, eg RPMI 1640 with 10% fetal bovine serum. The cells are first grown and allowed to attach further. The cells were then treated with one or more D at various varying concentrations.
It can be treated with a PP IV inhibitor and then pulsed with [ ³ H] thymidine to assess uptake, which is an indication of cell viability and proliferation. See U.S. Pat. No. 5,804,602.

While the present description, specific examples and data are representative of exemplary embodiments, they are provided by way of illustration and are not intended to be limiting of the invention. Should. Many variations and modifications within this invention will be apparent to those skilled in the art from the discussion, disclosure, and data contained herein.
Therefore, they are considered part of this invention.

[Brief description of drawings]

FIG. 1 is a graphical depiction of an evaluation using organotypic spinal motor neurons and threohydroxyaspartate (“THA”). Exposure of neurons with THA alone resulted in 55-60% death of neurons. When neurons were exposed to THA with 10 μM c-KPG, c-KPG rescued more than 50% of the neurons that would have been killed if exposed to THA alone.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 9/10 A61P 25/00 101 13/08 25/06 25/00 101 25/16 25/06 35 / 00 25/16 43/00 111 35/00 C07D 207/16 43/00 111 C07K 5/062 C07D 207/16 C12N 9/99 C07K 5/062 C07D 401/12 C12N 9/99 A61K 37/02 // C07D 401/12 37/64 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, TR), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ) , SD, SL, S , TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR , BY, BZ, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, 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, NO, NZ , PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Steiner, Joseph Mount Airy, 21771, Maryland, United States , Jupiter Eyeland Coat 3179 F Term (Reference) 4C063 AA01 BB09 CC10 CC12 DD03 DD29 EE01 4C069 AA17 4C084 AA02 AA07 BA25 CA59 DC32 MA17 MA52 MA55 MA66 NA14 ZA021 ZA021 ZA021 ZA02A ZA081 A07A07A07A02 A07A02 A07A02A07A02A07A02A07A02 NA14 ZA02 ZA08 ZA15 ZA36 ZA94 ZB26 4H045 AA10 AA30 BA11 DA56 EA21 FA10

Claims (30)

[Claims] 1. An inhibitor of dipeptidyl peptidase IV, which comprises a mimetic of proline and has an IC ₅₀ of 1 μM or less and a molecular weight of 500 or less. 2. The inhibitor according to claim 1, wherein the IC ₅₀ is 100 nM or less. 3. The inhibitor is strokes, tumors, ischemia.
ia), Parkinson's disease, amyotrophic
The inhibitor according to claim 1, which can be used for treating a central nervous system disorder selected from the group consisting of lateral sclerosis) and migraines. 4. A reversible inhibitor of dipeptidyl peptidase IV.
inhibitor) and having the following formula (I): Where X is CR2R3, O, S, NR4; provided that X is S,
Or when both X and X1 are CH ₂ , Z is O, A is CN, and R1 is H, then R is substituted with a C1-C9 straight or branched chain alkyl. X1 is CR2CR3, O, S, or NR4, provided that both X and X1 cannot be heteroatoms, and , X and X1 are both CH ₂ , and Z is O, and R 1 is NH ₂ , then when A is COOH, then R is not 1-methylpropyl and A is CN. In some cases, R is not cyclopentyl; A is H, COOH, or carboxylic acid isosteres, such as CN
, SO ₃ H, CONOH, PO ₃ R5R6, SO ₂ NHR7, tetrazole, amide, ester, and acid anhydride, provided that A is CN and R1 is NH ₂ , Z is O, and R is 1-
When it is methylpropyl, both X and X1 are not CH ₂ ; X and X1
Is not S; further X is not O; Z is O or S; R and R1 are H, C ₁ -C ₉ branched or straight chain alkyl, C ₂ -C ₉ branched or straight chain Independently selected from the group of functional groups consisting of alkenyl, C ₃ -C ₉ cycloalkyl, C ₅ -C ₇ cycloalkenyl, aryl, heteroaryl, and amino, where each of the functional groups is 1 or more. C ₁ -C ₉ straight or branched chain alkyl, aryl, heteroaryl, amino, halogen, carbonyl, C ₁ -C ₉ alkoxy, C ₂ -C ₉ alkenyloxy, phenoxy, benzyloxy, C ₃ -C ₈ cyclo. It can be substituted with alkyl, cyano, amido, thiol, trifluoromethyl, or hydroxy, where each of R and R1 can be the same or different; and R2, R3, R4, R5, R6, and R7, if present, are H, C ₁
To C ₉ branched or straight chain alkyl, C _{2 to} C ₉ branched or straight chain alkenyl, C _{3 to} C ₉ cycloalkyl, C _{5 to} C ₇ cycloalkenyl, aryl, heteroaryl, and amino. Independently selected from the group, wherein any of the above functional groups is also one or more C ₁ -C ₉ straight or branched chain alkyl, aryl, heteroaryl, amino, halogen, carbonyl, C ₁ -C ₉ alkoxy. , C ₂ -C ₉ alkenyloxy, phenoxy, benzyloxy, C ₃ -C ₈ cycloalkyl, cyano, amide, thiol,
Can be substituted with trifluoromethyl, or hydroxy, where R2,
Each of R3, R4, R5, R6, and R7, if present, can be the same or different. } The said inhibitor which has a center part structure represented by these. 5. The reversible inhibitor of claim 4, wherein the inhibitor has an IC ₅₀ of 1 μM or less and a molecular weight of 500 or less. 6. A reversible inhibitor of dipeptidyl peptidase IV, which is represented by the following formula (II): Where X is CR2R3, O, S, or NR4; A is H, COOH, or carboxylic acid isosteres, such as CN
, SO ₃ H, CONOH, PO ₃ R5R6, SO ₂ NHR7, tetrazole, amide, ester, and acid anhydride; and Z is O or S; R and R1 are , H, C ₁ -C ₉ branched or straight chain alkyl, C ₂ -C ₉ branched or straight chain alkenyl, C ₃ -C ₈ cycloalkyl, C ₅ -C ₇ cycloalkenyl, aryl, heteroaryl, and amino. Independently selected from the group of functional groups consisting of, wherein any of the above functional groups is one or more C _{1 to} C ₉ straight or branched chain alkyl, aryl, heteroaryl, amino, halogen, carbonyl, C ₁ -C ₉ alkoxy, C ₂ -C ₉ alkenyloxy, phenoxy, benzyloxy, C ₃ -C ₈ cycloalkyl, cyano, amido, thiol, trifluoromethyl, or substituted with hydroxy Is it possible, where each of R and R1 is can be the same or different; when and R2, R3, R4, R5, R6, and R7, in which it resides, H, C ₁
To C ₉ branched or straight chain alkyl, C _{2 to} C ₉ branched or straight chain alkenyl, C _{3 to} C ₈ cycloalkyl, C _{5 to} C ₇ cycloalkenyl, aryl, heteroaryl, and amino. Independently selected from the group, wherein any of the above functional groups is also one or more C ₁ -C ₉ straight or branched chain alkyl, aryl, heteroaryl, amino, halogen, carbonyl, C ₁ -C ₉ alkoxy. , C ₂ -C ₉ alkenyloxy, phenoxy, benzyloxy, C ₃ -C ₈ cycloalkyl, cyano, amide, thiol,
Can be substituted with trifluoromethyl, or hydroxy, where R2,
Each of R3, R4, R5, R6, and R7, if present, can be the same or different. } The said inhibitor which has a center part structure represented by these. 7. The reversible inhibitor of claim 6, wherein the inhibitor has an IC ₅₀ of 1 μM or less and a molecular weight of 500 or less. 8. A reversible inhibitor of dipeptidyl peptidase IV, which is represented by the following formula (III): Where A is H, COOH, or isosteres of carboxylic acids, such as CN, SO ₃ H, CONOH, PO ₃ R5R6, SO ₂ NHR7, tetrazole, amides, esters, and acid anhydrides. are those from one selected; Z is O or S; R, R1, R2, and R3 are H, C ₁ -C ₉ branched or straight chain alkyl, C ₂ -C ₉ branched or linear alkenyl, C ₃ -C ₈ cycloalkyl, C ₅ -C ₇ cycloalkenyl, aryl, independently selected from the group of functional groups consisting of heteroaryl, and amino, wherein any of the functional groups, 1 The above C _{1 to} C ₉ straight chain or branched chain alkyl,
Aryl, heteroaryl, amino, halogen, carbonyl, C ₁ -C ₉ alkoxy, C ₂ -C ₉ alkenyloxy, phenoxy, benzyloxy, C ₃ -C ₈ cycloalkyl, cyano, amide, thiol, trifluoromethyl, or Can be substituted with hydroxy, wherein each of R, R1, R2, and R3 can be the same or different; and R4, R5, R6, and R7, if present, H, C ₁ ~C ₉ branched or straight chain alkyl, C ₂ -C ₉ branched or straight chain alkenyl, C ₃ -C ₈ cycloalkyl, C ₅
To C ₇ cycloalkenyl, aryl, heteroaryl, and amino are independently selected from the group of functional groups, wherein any of the functional groups is one or more C _{1 to} C ₉ straight or branched chain alkyl. , Aryl, heteroaryl, amino, halogen, carbonyl, C ₁ -C ₉ alkoxy, C ₂ -C ₉ alkenyloxy, phenoxy, benzyloxy, C ₃ -C ₈ cycloalkyl, cyano, amide, thiol, trifluoromethyl, Or, it can be substituted with hydroxy, where each of R4, R5, R6, and R7, if present, can be the same or different.
} The said inhibitor which has a center part structure represented by these. 9. The reversible inhibitor of claim 8, wherein the inhibitor has an IC ₅₀ of 1 μM or less and a molecular weight of 500 or less. 10. A reversible inhibitor of dipeptidyl peptidase IV, which comprises:
The following formula (IV): Where X is CR2R3, O, S, or NR4; X ₁ is CR2R3, O, S, or NR4, provided that both X and X1 are
A cannot be a heteroatom; A is H, COOH, or a carboxylic acid isosteres, such as CN
, SO ₃ H, CONOH, PO ₃ R5R6, SO ₂ NHR7, tetrazole, an amide, an ester, and an acid anhydride; and R and R1 are H, C _{1 to} C ₉ min. branched or straight chain alkyl, C ₂ -C ₉ branched or straight chain alkenyl, C ₃ -C ₈ cycloalkyl, C ₅ -C ₇ cycloalkenyl, aryl, heteroaryl, and independently from the group of functional groups consisting of amino Where any of the above functional groups also has one or more C _{1 to} C ₉ straight or branched chain alkyl, aryl, heteroaryl, amino, halogen, carbonyl, C _{1 to} C ₉ alkoxy, C ₂ C ₉ alkenyloxy, phenoxy, benzyloxy, C ₃ -C ₈ cycloalkyl, cyano, amido, thiol, it can be substituted by trifluoromethyl, or hydroxy, wherein Each R and R1 is can be the same or different; and R2, R3, R4, R5, R6 and R7, when present, H, C ₁ ~
C ₉ branched or straight chain alkyl, C ₂ -C ₉ branched or straight chain alkenyl, C ₃ -C ₈ cycloalkyl, C ₅ -C ₇ cycloalkenyl, aryl, a group of functional groups consisting of heteroaryl, and amino Independently selected from one or more C ₁ -C ₉ straight or branched chain alkyl, aryl, heteroaryl, amino, halogen, carbonyl, C ₁ -C ₉ alkoxy, It can be substituted with C ₂ -C ₉ alkenyloxy, phenoxy, benzyloxy, C ₃ -C ₈ cycloalkyl, cyano, amido, thiol, trifluoromethyl, or hydroxy, where R 2, R 3
, R4, R5, R6, and R7, if present, can be the same or different. } The said inhibitor which has a center part structure represented by these. 11. The reversible inhibitor of claim 10, wherein the inhibitor has an IC ₅₀ of 1 μM or less and a molecular weight of 500 or less. 12. A method of treating a patient having a central nervous system disorder, comprising administering to said patient a therapeutically effective amount of a reversible inhibitor of dipeptidyl peptidase IV. The inhibitor has the following formula (I): Where X is CR2R3, O, S, NR4; X ₁ is CR2CR3, O, S, or NR4, provided that both X and X1 cannot be heteroatoms; A is H, COOH, or carboxylic acid isosteres, such as CN
, SO ₃ H, CONOH, PO ₃ R5R6, SO ₂ NHR7, tetrazole, amide, ester, and acid anhydride; and Z is O or S; R and R1 are , H, C ₁ -C ₉ branched or straight chain alkyl, C ₂ -C ₉ branched or straight chain alkenyl, C ₃ -C ₈ cycloalkyl, C ₅ -C ₇ cycloalkenyl, aryl, heteroaryl, and amino. Independently selected from the group of functional groups consisting of, wherein any of the above functional groups is one or more C _{1 to} C ₉ straight or branched chain alkyl, aryl, heteroaryl, amino, halogen, carbonyl, C ₁ -C ₉ alkoxy, C ₂ -C ₉ alkenyloxy, phenoxy, benzyloxy, C ₃ -C ₈ cycloalkyl, cyano, amido, thiol, trifluoromethyl, or substituted with hydroxy Is it possible, where each of R and R1 is can be the same or different; and R2, R3, R4, R5, R6 and R7, when present, H, C ₁ ~
C ₉ branched or straight chain alkyl, C ₂ -C ₉ branched or straight chain alkenyl, C ₃ -C ₈ cycloalkyl, C ₅ -C ₇ cycloalkenyl, aryl, a group of functional groups consisting of heteroaryl, and amino Independently selected from one or more C ₁ -C ₉ straight or branched chain alkyl, aryl, heteroaryl, amino, halogen, carbonyl, C ₁ -C ₉ alkoxy. , C ₂ -C ₉ alkenyloxy, phenoxy, benzyloxy, C ₃ -C ₈ cycloalkyl, cyano, amide, thiol,
Can be substituted with trifluoromethyl, or hydroxy, where R2,
Each of R3, R4, R5, R6, and R7, if present, can be the same or different. } The said therapeutic method which has a central part structure represented by these. 13. The method of claim 12, wherein the inhibitor has an IC ₅₀ of 1 μM or less and a molecular weight of 500 or less. 14. R is C1 when X is S, or both X and X1 are CH ₂ , Z is O, A is CN, and R1 is H.
~C9 straight or branched chain alkyl substituted NH, or rather NH substituted by C3~C7 cycloalkyl; and both of X and X1 is CH _2, and Z is O, and when R1 is NH _2, when a is COOH, R 1
- If not methyl propyl and A is CN, R is not cyclopentyl; and, A is CN, and R1 is NH _2, and Z is O, and R is 1-methylpropyl If it is, rather than CH ₂ both X and X1;
13. The method of claim 12, wherein X and X1 are not S; and X is not O. 15. A method of treating a patient having a central nervous system disorder comprising administering to said patient a therapeutically effective amount of a reversible inhibitor of dipeptidyl peptidase IV. The inhibitor has the following formula (II): Where X is CR2R3, O, S, or NR4; A is H, COOH, or carboxylic acid isosteres, such as CN
, SO ₃ H, CONOH, PO ₃ R5R6, SO ₂ NHR7, tetrazole, amide, ester, and acid anhydride; and Z is O or S; R and R1 are , H, C ₁ -C ₉ branched or straight chain alkyl, C ₂ -C ₉ branched or straight chain alkenyl, C ₃ -C ₈ cycloalkyl, C ₅ -C ₇ cycloalkenyl, aryl, heteroaryl, and amino. Independently selected from the group of functional groups consisting of, wherein any of the above functional groups is one or more C _{1 to} C ₉ straight or branched chain alkyl, aryl, heteroaryl, amino, halogen, carbonyl, C ₁ -C ₉ alkoxy, C ₂ -C ₉ alkenyloxy, phenoxy, benzyloxy, C ₃ -C ₈ cycloalkyl, cyano, amido, thiol, trifluoromethyl, or substituted with hydroxy Is it possible, where each of R and R1 is can be the same or different; when and R2, R3, R4, R5, R6, and R7, in which it resides, H, C ₁
To C ₉ branched or straight chain alkyl, C _{2 to} C ₉ branched or straight chain alkenyl, C _{3 to} C ₈ cycloalkyl, C _{5 to} C ₇ cycloalkenyl, aryl, heteroaryl, and amino. Independently selected from the group, wherein any of the above functional groups is also one or more C ₁ -C ₉ straight or branched chain alkyl, aryl, heteroaryl, amino, halogen, carbonyl, C ₁ -C ₉ alkoxy. , C ₂ -C ₉ alkenyloxy, phenoxy, benzyloxy, C ₃ -C ₈ cycloalkyl, cyano, amide, thiol,
Can be substituted with trifluoromethyl, or hydroxy, where R2,
Each of R3, R4, R5, R6, and R7, if present, can be the same or different. } The said therapeutic method which has a central part structure represented by these. 16. The method of claim 15, wherein the inhibitor has an IC ₅₀ of 1 μM or less and a molecular weight of 500 or less. 17. A method of treating a patient having a central nervous system disorder, comprising administering to said patient a therapeutically effective amount of a reversible inhibitor of dipeptidyl peptidase IV. The inhibitor has the following formula (III): Where A is H, COOH, or isosteres of carboxylic acids, such as CN, SO ₃ H, CONOH, PO ₃ R5R6, SO ₂ NHR7, tetrazole, amides, esters, and acid anhydrides. are those from one selected; Z is O or S; R, R1, R2, and R3 are H, C ₁ -C ₉ branched or straight chain alkyl, C ₂ -C ₉ branched or linear alkenyl, C ₃ -C ₈ cycloalkyl, C ₅ -C ₇ cycloalkenyl, aryl, independently selected from the group of functional groups consisting of heteroaryl, and amino, wherein any of the functional groups, 1 The above C _{1 to} C ₉ straight chain or branched chain alkyl,
Aryl, heteroaryl, amino, halogen, carbonyl, C ₁ -C ₉ alkoxy, C ₂ -C ₉ alkenyloxy, phenoxy, benzyloxy, C ₃ -C ₈ cycloalkyl, cyano, amide, thiol, trifluoromethyl, or Can be substituted with hydroxy, wherein each of R, R1, R2, and R3 can be the same or different; and R4, R5, R6, and R7 can be when it is present , H, C ₁ -C ₉ branched or linear alkyl, C ₂ -C ₉ branched or linear alkenyl, C ₃ -C ₈ cycloalkyl, C ₅
To C ₇ cycloalkenyl, aryl, heteroaryl, and amino are independently selected from the group of functional groups, wherein any of the functional groups is one or more C _{1 to} C ₉ straight or branched chain alkyl. , Aryl, heteroaryl, amino, halogen, carbonyl, C ₁ -C ₉ alkoxy, C ₂ -C ₉ alkenyloxy, phenoxy, benzyloxy, C ₃ -C ₈ cycloalkyl, cyano, amide, thiol, trifluoromethyl, Or, it can be substituted with hydroxy, where each of R4, R5, R6, and R7, if present, can be the same or different.
} The said therapeutic method which has a central part structure represented by these. 18. The method of claim 17, wherein the inhibitor has an IC ₅₀ of 1 μM or less and a molecular weight of 500 or less. 19. A method of treating a patient having a central nervous system disorder, comprising administering to said patient a therapeutically effective amount of a reversible inhibitor of dipeptidyl peptidase IV. The inhibitor has the following formula (IV): Where X is CR2R3, O, S, or NR4; X ₁ is CR2R3, O, S, or NR4, provided that both X and X1 are
A cannot be a heteroatom; A is H, COOH, or a carboxylic acid isosteres, such as CN
, SO ₃ H, CONOH, PO ₃ R5R6, SO ₂ NHR7, tetrazole, an amide, an ester, and an acid anhydride; and R and R1 are H, C _{1 to} C ₉ min. branched or straight chain alkyl, C ₂ -C ₉ branched or straight chain alkenyl, C ₃ -C ₈ cycloalkyl, C ₅ -C ₇ cycloalkenyl, aryl, heteroaryl, and independently from the group of functional groups consisting of amino Where any of the above functional groups also has one or more C _{1 to} C ₉ straight or branched chain alkyl, aryl, heteroaryl, amino, halogen, carbonyl, C _{1 to} C ₉ alkoxy, C ₂ C ₉ alkenyloxy, phenoxy, benzyloxy, C ₃ -C ₈ cycloalkyl, cyano, amido, thiol, it can be substituted by trifluoromethyl, or hydroxy, wherein Each R and R1 is can be the same or different; and R2, R3, R4, R5, R6 and R7, when present, H, C ₁ ~
C ₉ branched or straight chain alkyl, C ₂ -C ₉ branched or straight chain alkenyl, C ₃ -C ₈ cycloalkyl, C ₅ -C ₇ cycloalkenyl, aryl, a group of functional groups consisting of heteroaryl, and amino Independently selected from one or more C ₁ -C ₉ straight or branched chain alkyl, aryl, heteroaryl, amino, halogen, carbonyl, C ₁ -C ₉ alkoxy, It can be substituted with C ₂ -C ₉ alkenyloxy, phenoxy, benzyloxy, C ₃ -C ₈ cycloalkyl, cyano, amido, thiol, trifluoromethyl, or hydroxy, where R 2, R 3
, R4, R5, R6, and R7, if present, can be the same or different. } The said therapeutic method which has a central part structure represented by these. 20. The method of claim 19, wherein the inhibitor has an IC ₅₀ of 1 μM or less and a molecular weight of 500 or less. 21. A method of treating a patient having a central nervous system disorder, comprising administering to said patient a therapeutically effective amount of an inhibitor of dipeptidyl peptidase IV. 22. The method of claim 21, wherein the inhibitor comprises a proline mimetic and has an IC ₅₀ of 1 μM or less and a molecular weight of 700 or less. 23. The inhibitor has a central structure of formula (I), formula (II)
), The core structure represented by formula (III), and the formula (IV)
22. A core structure selected from the group consisting of core structures represented by:
The method described in. 24. The method of claim 21, wherein the inhibitor is reversible. 25. The method of claim 21, wherein the central nervous system disease is selected from the group consisting of stroke, tumor, ischemia, Parkinson's disease, amyotrophic lateral sclerosis, and migraine. 26. Strokes, tumors, ischemia, Parkinson's disease, memory loss, hearing loss.
oss), vision loss, migraines, brain injury,
Spinal cord injury, Alzheimer's disease,
Amyotrophic lateral, multiple sclerosis
), Diabetic neuropathy, and prostate abnorm
alities), a method of treating a patient having a disease selected from the group consisting of:
Such a method comprising administering to a patient a therapeutically effective amount of an inhibitor of dipeptidyl peptidase IV. 27. The method of claim 26, wherein the inhibitor comprises a proline mimic and has an IC ₅₀ of 1 μM or less and a molecular weight of 700 or less. 28. The inhibitor has a central structure of formula (I), formula (II)
), The core structure represented by formula (III), and the formula (IV)
27. A core structure selected from the group consisting of core structures represented by:
The method described in. 29. A method of using a reversible inhibitor of DPP-IV, comprising administering to a patient suffering from a central nervous system disorder a pharmaceutically effective amount of said inhibitor, wherein , The inhibitor has the following formula: Where R is NH—R ^I ; R ^I is: C ₁ -C ₁₂ straight or branched chain alkyl; C ₃ -C ₇ cycloalkyl; CH ₂ —CH ₂ —NH—R ^II ; be or ^{_{CH 2 -CH 2 -CH 2 -R V}} ;; CH 2 -CH 2 -R III; CH 2 -CH 2 -CHR IV -R IV R II is an optionally one or two positions, A pyridine ring substituted with halogen, trifluoromethyl, cyano, or nitro; or a pyrimidine ring optionally substituted in one position with halogen, trifluoromethyl, cyano, or nitro; R ^III is the cases 1 to 3 positions, halogen, or C ₁ -C be ₃ phenyl ring substituted with an alkoxy; each R ^IV, independently of one positions by halogen, or C ₁ ~
A phenyl ring substituted with C ₃ alkoxy; and R ^V is a 2-oxopyrrolidine group, or a C ₂ -C ₄ alkoxy group. } The method represented by 30. A method of using a reversible inhibitor of DPP-IV comprising administering to a patient suffering from a central nervous system disease a pharmaceutically effective amount of said inhibitor, wherein , The inhibitor has the following formula: {In the formula, R is an NH-R ^I; R ^I is: optionally, hydroxy, acetyl, C ₁ -C ₃ alkoxy, or C ₁ ~
C ₁ -C ₁₂ straight or branched chain alkyl substituted with C ₃ hydroxyalkyl; optionally substituted with hydroxy, acetyl, C ₁ -C ₃ alkoxy, or C ₁ -C ₃ hydroxyalkyl, C ₃ -C ₁₂ cycloalkyl; adamantyl; indanyl; 1 optionally; bicycloheptyl optionally substituted optionally with 1 to 3 positions by methyl; pyrrolidine substituted by benzyl optionally; optionally piperidyl substituted with benzyl Phenyl substituted on three positions with halogen, methoxy, trifluoromethyl; pyridyl optionally substituted on one to three positions with halogen, trifluoromethyl, nitro; or optionally halogen, trifluoromethyl, been pyrimidyl substituted with nitro; substituted with R ^IV, further optionally in hydroxy Is conversion, C ₁ -C ₃ straight or branched chain alkyl; be or ^{_{(CH 2) 1~3 -NR II R}} III; R II is hydrogen or methyl; R ^III is optionally Phenyl substituted with CN, or pyridyl optionally substituted with CN; and R ^IV is a group selected from phenyl, naphthyl, cyclohexenyl, pyridyl, pyrimidyl, adamantyl, phenoxy, wherein: Are optionally substituted at one or two positions with phenyl sulfide substituted with ethoxy, methoxy, halogen, phenyl sulfide, or hydroxymethyl. } The method represented by