KR20050019786A - Use of an alpha2delta ligand such as gabapentin or pregabalin for treating attention deficit hyperactivity disorder - Google Patents

Abstract

The present invention relates to a method of treating ADHD by administering an alpha 2 delta ligand such as gabapentin or pregabalin, or a pharmaceutically acceptable salt thereof.

Description

USE OF AN ALPHA2DELTA LIGAND SUCH AS GABAPENTIN OR PREGABALIN FOR TREATING ATTENTION DEFICIT HYPERACTIVITY DISORDER}

The present invention relates to a method for preventing or treating attention deficit hyperactivity disorder (“ADHD”) by administering a compound that exhibits activity as an alpha 2 delta ligand (α 2δ ligand). Such compounds have affinity for the α2δ subunit of calcium channels. In addition, such compounds have been mentioned in the literature as gamma-aminobutyric acid (GABA) analogs.

Attention deficit hyperactivity disorder (ADHD) is estimated to occur in 3-5% of school-age children. Attentional symptoms of ADHD can be successfully treated using psychomotor stimulants such as methylphenidate (Ritalin). Clonidine, an α ₂ -adrenergic receptor agonist, treats aggressive and rebellious symptoms. Since both methylphenidate and clonidine are subject to significant side effects, it is important to find other drugs with similar or superior efficacy with fewer side effects.

Since ADHD can be characterized as a dysregulation of catecholamine neurotransmission in the executive region of the brain, such as the prefrontal cortex, the drug action that modulates this neurotransmission may be potentially associated with ADHD treatment. In this regard, alpha2delta ligands, including gabapentin and pregabalin, may be effective in treating such disorders. This assumption is based on our previous observation that gabapentin and pregabalin appear to preferentially reduce neurotransmitter release induced by stimuli that are considered to be pathological in nature (J. Pharmacol. Exp. Titer 295: 1086-1093, 2000). Thus, ADHD is sensitive to alpha2delta ligands alone or in combination with stimulants (eg ritalin) or non-irritants (eg atomoxetine, GT-2331 (Perceptin)). It may be an indication.

ADHD is one of the most common childhood psychiatric disorders, and it is often underrecognized and common psychiatric disorders in adults (Spencer T, 1998). This disorder, beginning in childhood, can be followed by a manifestation of symptoms (eg, hyperactivity and / or impulsivity) throughout life (Schweitzer JB, 2001). Signs may change as ADHD is expressed in adulthood from preschool age (Cantwell DP, 1996; Elia J, 1999; Nolan EE, 2001).

Diagnosis of ADHD is based on clinical evaluation (Dulcan M, 1997; National Institutes of Health, 1998). "The essential characteristic of ADHD is the persistent pattern of distraction and / or hyperactivity-impulse, which is more frequent and severe than typically observed in individuals with equal development" (Diagnostic and Statistical Manual of Mental Disorders (DSM-IV ), Americanpsychiatric Association, Washington, DC, 1994). To be diagnosed with ADHD, a patient must show symptoms of ADHD causing injury before age 7 and the symptoms must last at least two places (eg, school [or work] and home) for at least six months. (See DSM-IV).

Several alpha 2 delta ligands are known. Gabapentin, a cyclic alpha2delta ligand, is currently commercially available (Neurontin®) and Warner-Lambert Company, which is widely clinically used to treat epilepsy and neuropathic pain. Used. Such cyclic alpha2delta ligands are described in US Pat. No. 4,024,175, registered May 17, 1977 and US Pat. No. 4,087,544, registered May 2, 1978. A further series of alpha2delta ligands are described in US Patent No. 5,563,175, filed Oct. 8, 1996, US Patent No. 6,316,638, filed Jan. 13, 2001, US Provisional Patent Application No. 60, January 31, 2002 / 353,632, European Patent Application EP 1112253 published July 4, 2001, PCT Patent Application WO 99/08671 published February 25, 1999 and PCT Patent Application WO 99/61424 published December 2, 1999 It is described in. These patents and applications are hereby incorporated by reference in their entirety.

Summary of the Invention

The present invention provides a method for preventing or treating ADHD in a mammal with ADHD comprising administering a therapeutically effective amount of an alpha 2delta ligand or a pharmaceutically acceptable salt thereof. In the present specification, this is sometimes referred to as the "method of the present invention".

Preferred embodiments of the process of the invention use an alpha 2 delta ligand, which is a cyclic amino acid compound of formula (I) and a pharmaceutically acceptable salt thereof.

In said formula, R <_1> is hydrogen or lower alkyl, n is an integer of 4-6. A particularly preferred embodiment uses a compound of formula I, wherein R ₁ is hydrogen and n is 5, which is 1- (aminomethyl) -cyclohexane acetic acid and is commonly known as gabapentin. Other preferred alpha 2delta ligands or pharmaceutically acceptable salts thereof are compounds of formula I, wherein the cyclic ring is substituted with alkyl such as, for example, methyl or ethyl. Typical of such compounds include (1-aminomethyl-3-methylcyclohexyl) acetic acid, (1-aminomethyl-3-methylcyclopentyl) acetic acid and (1-aminomethyl-3,4-dimethylcyclopentyl) acetic acid do.

In another preferred embodiment, the method of the present invention uses the alpha 2 delta ligand of formula II or a pharmaceutically acceptable salt thereof.

In the above formula,

R ₁ is straight or branched unsubstituted alkyl having 1 to 6 carbon atoms, unsubstituted phenyl, or unsubstituted cycloalkyl having 3 to 6 carbon atoms;

R ₂ is hydrogen or methyl;

R ₃ is hydrogen, methyl or carboxyl.

Diastereomers and enantiomers of the compounds of formula II can be used in the methods of the invention.

Particularly preferred embodiments of the process of the invention are the (R), (S) or (R, S) isomers wherein both R ₂ and R ₃ are hydrogen and R ₁ is — (CH ₂ ) _0-2 —iC ₄ A compound of formula II is used, which is H ₉ .

A more preferred embodiment of the process of the invention is named 3-aminomethyl-5-methyl-hexanoic acid, or in particular (S) -3- (aminomethyl) -5-methylhexanoic acid and is currently generally prega Compounds of formula II known as valine are used. Pregabalin is also known as "CI-1008" and "S-(+)-3-IBG".

Another preferred embodiment of the process of the invention uses a compound of formula (II) named 3- (1-aminoethyl) -5-methylheptanoic acid or 3- (1-aminoethyl) -5-methylhexanoic acid .

Another preferred embodiment of the process of the invention uses an alpha 2 delta ligand, which is a compound of formula III, IIIC, IIIF, IIIG, or IIIH, or a pharmaceutically acceptable salt thereof.

In the above formula,

n is an integer from 0 to 2;

m is an integer from 0 to 3;

R is sulfonamide, amide, phosphonic acid, heterocycle, sulfonic acid or hydroxamic acid;

R ₁ to R ₁₄ are hydrogen, straight or branched alkyl having 1 to 6 carbon atoms, unsubstituted or substituted with halogen, alkyl, alkoxy, hydroxy, carboxy, carboalkoxy, trifluoromethyl and nitro Each independently selected from substituted benzyl or phenyl;

A '

, , ,

And

Bridged ring selected from

here Is the point of attachment;

Z ₁ to Z ₄ are each independently selected from hydrogen and methyl;

o is an integer from 1 to 4;

p is an integer of 0-2.

Another preferred embodiment of the method of the invention,

(1-aminomethyl-cyclohexylmethyl) -phosphonic acid;

(1R-trans) (1-Aminomethyl-3-methyl-cyclohexylmethyl) -phosphonic acid;

(Trans) (1-aminomethyl-3,4-dimethyl-cyclopentylmethyl) -phosphonic acid;

(1R-trans) (1-Aminomethyl-3-methyl-cyclopentylmethyl) -phosphonic acid;

(1S-cis) (1-aminomethyl-3-methyl-cyclopentylmethyl) -phosphonic acid;

(1S-trans) (1-Aminomethyl-3-methyl-cyclopentylmethyl) -phosphonic acid;

(1R-cis) (1-aminomethyl-3-methyl-cyclopentylmethyl) -phosphonic acid;

(1α, 3α, 4α) (1-aminomethyl-3,4-dimethyl-cyclopentylmethyl) -phosphonic acid;

(1α, 3β, 4β) (1-aminomethyl-3,4-dimethyl-cyclopentylmethyl) -phosphonic acid;

(R) (1-Aminomethyl-3, 3-dimethyl-cyclopentylmethyl) -phosphonic acid;

(S) (1-Aminomethyl-3, 3-dimethyl-cyclopentylmethyl) -phosphonic acid;

(1-aminomethyl-3,3-dimethyl-cyclobutylmethyl) -phosphonic acid;

2- (1-aminomethyl-cyclohexyl) -N-hydroxy-acetamide;

(1S-trans) 2- (1-Aminomethyl-3-methyl-cyclohexyl) -N-hydroxy-acetamide;

(Trans) 2- (1-aminomethyl-3,4-dimethyl-cyclopentyl) -N-hydroxy-acetamide;

(1S-cis) 2- (1-aminomethyl-3-methyl-cyclopentyl) -N-hydroxy-acetamide;

(1R-trans) 2- (1-Aminomethyl-3-methyl-cyclopentyl) -N-hydroxy-acetamide;

(1R-cis) 2- (1-aminomethyl-3-methyl-cyclopentyl) -N-hydroxy-acetamide;

(1S-trans) 2- (1-Aminomethyl-3-methyl-cyclopentyl) -N-hydroxy-acetamide;

(1α, 3α, 4α) 2- (1-aminomethyl-3,4-dimethyl-cyclopentyl) -N-hydroxy-acetamide;

(1α, 3β, 4β) 2- (1-aminomethyl-3,4-dimethyl-cyclopentyl) -N-hydroxy-acetamide;

(S) 2- (1-Aminomethyl-3,3-dimethyl-cyclopentyl) -N-hydroxy-acetamide;

(R) 2- (1-Aminomethyl-3,3-dimethyl-cyclopentyl) -N-hydroxy-acetamide;

2- (1-aminomethyl-3,3-dimethyl-cyclobutyl) -N-hydroxy-acetamide;

N- [2- (1-Aminomethyl-cyclohexyl) -ethyl] -methanesulfonamide;

(1S-cis) N- [2- (1-aminomethyl-3-methyl-cyclohexyl) -ethyl] -methanesulfonamide;

(Trans) N- [2- (1-aminomethyl-3,4-dimethyl-cyclopentyl) -ethyl] -methanesulfonamide;

(1S-cis) N- [2- (1-aminomethyl-3-methyl-cyclopentyl) -ethyl] -methanesulfonamide;

(1R-trans) N- [2- (1-Aminomethyl-3-methyl-cyclopentyl) -ethyl] -methanesulfonamide;

(1R-cis) N- [2- (1-aminomethyl-3-methyl-cyclopentyl) -ethyl] -methanesulfonamide;

(1S-cis) N- [2- (1-aminomethyl-3-methyl-cyclopentyl) -ethyl] -methanesulfonamide;

(1α, 3α, 4α) N- [2- (1-aminomethyl-3,4-dimethyl-cyclopentyl) -ethyl] -methanesulfonamide;

(1α, 3β, 4β) N- [2- (1-aminomethyl-3,4-dimethyl-cyclopentyl) -ethyl] -methanesulfonamide;

(S) N- [2- (1-Aminomethyl-3, 3-dimethyl-cyclopentyl) -ethyl] -methanesulfonamide;

(R) N- [2- (1-Aminomethyl-3, 3-dimethyl-cyclopentyl) -ethyl] -methanesulfonamide;

N- [2- (1-Aminomethyl-3,3-dimethyl-cyclobutyl) -ethyl] -methanesulfonamide;

(1S-cis) 3- (1-aminomethyl-3-methyl-cyclohexylmethyl) -4H- [1,2,4] oxadiazol-5-one;

(Trans) 3- (1-aminomethyl-3,4-dimethyl-cyclopentylmethyl) -4H- [1,2,4] oxadiazol-5-one;

(1S-cis) 3- (1-aminomethyl-3-methyl-cyclopentylmethyl) -4H- [1,2,4] oxadiazol-5-one;

(1R-trans) 3- (1-Aminomethyl-3-methyl-cyclopentylmethyl) -4H- [1,2,4] oxadiazol-5-one;

(1R-cis) 3- (1-aminomethyl-3-methyl-cyclopentylmethyl) -4H- [1,2,4] oxadiazol-5-one;

(1S-trans) 3- (1-Aminomethyl-3-methyl-cyclopentylmethyl) -4H- [1,2,4] oxadiazol-5-one;

(1α, 3α, 4α) 3- (1-aminomethyl-3,4-dimethyl-cyclopentylmethyl) -4H- [1,2,4] oxadiazol-5-one;

(1α, 3β, 4β) 3- (1-aminomethyl-3,4-dimethyl-cyclopentylmethyl) -4H- [1,2,4] oxadiazol-5-one;

(S) 3- (1-aminomethyl-3,3-dimethyl-cyclopentylmethyl) -4H- [1,2,4] oxadiazol-5-one;

(R) 3- (1-aminomethyl-3,3-dimethyl-cyclopentylmethyl) -4H- [1,2,4] oxadiazol-5-one;

3- (1-aminomethyl-3,3-dimethyl-cyclobutylmethyl) -4H- [1,2,4] oxadiazol-5-one;

3- (1-aminomethyl-cyclohexylmethyl) -4H- [1,2,4] oxadiazole-5-thione;

(1S-cis) 3- (1-aminomethyl-3-methyl-cyclohexylmethyl) -4H- [1,2,4] oxadiazole-5-thione;

(Trans) 3- (1-aminomethyl-3,4-dimethyl-cyclopentylmethyl) -4H- [1,2,4] oxadiazole-5-thione;

(1S-cis) 3- (1-aminomethyl-3-methyl-cyclopentylmethyl) -4H- [1,2,4] oxadiazole-5-thione;

(1R-trans) 3- (1-Aminomethyl-3-methyl-cyclopentylmethyl) -4H- [1,2,4] oxadiazole-5-thione;

(1R-cis) 3- (1-aminomethyl-3-methyl-cyclopentylmethyl) -4H- [1,2,4] oxadiazole-5-thione;

(1S-trans) 3- (1-Aminomethyl-3-methyl-cyclopentylmethyl) -4H- [1,2,4] oxadiazole-5-thione;

(1α, 3α, 4α) 3- (1-aminomethyl-3,4-dimethyl-cyclopentylmethyl) -4H- [1,2,4] oxadiazole-5-thione;

(1α, 3β, 4β) 3- (1-aminomethyl-3,4-dimethyl-cyclopentylmethyl) -4H- [1,2,4] oxadiazole-5-thione;

(S) 3- (1-aminomethyl-3,3-dimethyl-cyclopentylmethyl) -4H- [1,2,4] oxadiazole-5-thione;

(R) 3- (1-Aminomethyl-3,3-dimethyl-cyclopentylmethyl) -4H- [1,2,4] oxadiazole-5-thione;

3- (1-aminomethyl-3,3-dimethyl-cyclobutylmethyl) -4H- [1,2,4] oxadiazole-5-thione;

C- [1- (1H-tetrazol-5-ylmethyl) -cyclohexyl] -methylamine;

(1S-cis) C- [3-methyl-1- (1H-tetrazol-5-ylmethyl) -cyclohexyl] -methylamine;

(Trans) C- [3,4-dimethyl-1- (1H-tetrazol-5-ylmethyl) -cyclopentyl] -methylamine;

(1S-cis) C- [3-methyl-1- (1H-tetrazol-5-ylmethyl) -cyclopentyl] -methylamine;

(1R-trans) C- [3-methyl-1- (1H-tetrazol-5-ylmethyl) -cyclopentyl] -methylamine;

(1R-cis) C- [3-methyl-1- (1H-tetrazol-5-ylmethyl) -cyclopentyl] -methylamine;

(1S-trans) C- [3-methyl-1- (1H-tetrazol-5-ylmethyl) -cyclopentyl] -methylamine;

(1α, 3α, 4α) C- [3,4-dimethyl-1- (1H-tetrazol-5-ylmethyl) -cyclopentyl] -methylamine;

(1α, 3β, 4β) C- [3,4-dimethyl-1- (1H-tetrazol-5-ylmethyl) -cyclopentyl] -methylamine;

(S) C- [3,3-dimethyl-1- (1H-tetrazol-5-ylmethyl) -cyclopentyl] -methylamine;

(R) C- [3,3-dimethyl-1- (1H-tetrazol-5-ylmethyl) -cyclopentyl] -methylamine;

C- [3,3-dimethyl-1- (1H-tetrazol-5-ylmethyl) -cyclobutyl] -methylamine;

N- [2- (1-Aminomethyl-cyclohexyl) -ethyl] -C, C, C- trifluoro- methanesulfonamide;

(1S-cis) N- [2- (1-aminomethyl-3-methyl-cyclohexyl) -ethyl] -C, C, C-trifluoro-methanesulfonamide;

(Trans) N- [2- (1-aminomethyl-3,4-dimethyl-cyclopentyl) -ethyl] -C, C, C- trifluoro- methanesulfonamide;

(1R-cis) N- [2- (1-aminomethyl-3-methyl-cyclopentyl) -ethyl] -C, C, C-trifluoro-methanesulfonamide;

(1S-trans) N- [2- (1-Aminomethyl-3-methyl-cyclopentyl) -ethyl] -C, C, C- trifluoro- methanesulfonamide;

(1S-cis) N- [2- (1-aminomethyl-3-methyl-cyclopentyl) -ethyl] -C, C, C-trifluoro-methanesulfonamide;

(1R-trans) N- [2- (1-aminomethyl-3-methyl-cyclopentyl) -ethyl] -C, C, C-trifluoro-methanesulfonamide;

(1α, 3α, 4α) N- [2- (1-aminomethyl-3,4-dimethyl-cyclopentyl) -ethyl] -C, C, C-trifluoro-methanesulfonamide;

(1α, 3β, 4β) N- [2- (1-aminomethyl-3,4-dimethyl-cyclopentyl) -ethyl] -C, C, C-trifluoro-methanesulfonamide;

(S) N- [2- (1-aminomethyl-3,3-dimethyl-cyclopentyl) -ethyl] -C, C, C-trifluoro-methanesulfonamide;

(R) N- [2- (1-Aminomethyl-3,3-dimethyl-cyclopentyl) -ethyl] -C, C, C-trifluoro-methanesulfonamide;

N- [2- (1-Aminomethyl-3,3-dimethyl-cyclobutyl) -ethyl] -C, C, C-trifluoro-methanesulfonamide;

3- (1-aminomethyl-cyclohexylmethyl) -4H- [1,2,4] thiadiazol-5-one;

(1S-cis) 3- (1-aminomethyl-3-methyl-cyclohexylmethyl) -4H- [1,2,4] thiadiazol-5-one;

(Trans) 3- (1-aminomethyl-3,4-dimethyl-cyclopentylmethyl) -4H- [1,2,4] thiadiazol-5-one;

(1R-cis) 3- (1-aminomethyl-3-methyl-cyclopentylmethyl) -4H- [1,2,4] thiadiazol-5-one;

(1S-trans) 3- (1-Aminomethyl-3-methyl-cyclopentylmethyl) -4H- [1,2,4] thiadiazol-5-one;

(1S-cis) 3- (1-aminomethyl-3-methyl-cyclopentylmethyl) -4H- [1,2,4] thiadiazol-5-one;

(1R-trans) 3- (1-Aminomethyl-3-methyl-cyclopentylmethyl) -4H- [1,2,4] thiadiazol-5-one;

(1α, 3α, 4α) 3- (1-aminomethyl-3,4-dimethyl-cyclopentylmethyl) -4H- [1,2,4] thiadiazol-5-one;

(1α, 3β, 4β) 3- (1-aminomethyl-3,4-dimethyl-cyclopentylmethyl) -4H- [1,2,4] thiadiazol-5-one;

(S) 3- (1-aminomethyl-3,3-dimethyl-cyclopentylmethyl) -4H- [1,2,4] thiadiazol-5-one;

(R) 3- (1-aminomethyl-3,3-dimethyl-cyclopentylmethyl) -4H- [1,2,4] thiadiazol-5-one;

3- (1-aminomethyl-3,3-dimethyl-cyclobutylmethyl) -4H- [1,2,4] thiadiazol-5-one;

C- [1- (2-oxo-2,3-dihydro-2λ ^4- [1,2,3,5] oxathiadiazol- ⁴ -ylmethyl) -cyclohexyl] -methylamine;

(1S-cis) C- [3-methyl-1- (2-oxo-2,3-dihydro-2λ ^4- [1,2,3,5] oxathiadiazol- ⁴ -ylmethyl) -cyclo Hexyl] -methylamine;

(Trans) C- [3,4-dimethyl-1- (2-oxo-2,3-dihydro-2λ ^4- [1,2,3,5] oxathiadiazol- ⁴ -ylmethyl) -cyclo Pentyl] -methylamine;

(1S-cis) C- [3-methyl-1- (2-oxo-2,3-dihydro-2λ ^4- [1,2,3,5] oxathiadiazol- ⁴ -ylmethyl) -cyclo Pentyl] -methylamine;

(1R-trans) C- [3-methyl-1- (2-oxo-2,3-dihydro-2λ ^4- [1,2,3,5] oxathiadiazol- ⁴ -ylmethyl) -cyclo Pentyl] -methylamine;

(1R-cis) C- [3-methyl-1- (2-oxo-2,3-dihydro-2λ ^4- [1,2,3,5] oxathiadiazol- ⁴ -ylmethyl) -cyclo Pentyl] -methylamine;

(1S-trans) C- [3-methyl-1- (2-oxo-2,3-dihydro-2λ ^4- [1,2,3,5] oxathiadiazol- ⁴ -ylmethyl) -cyclo Pentyl] -methylamine;

(1α, 3α, 4α) C- [3,4-dimethyl-1- (2-oxo-2,3-dihydro-2λ ^4- [1,2,3,5] oxathiadiazol- ⁴ -yl Methyl) -cyclopentyl] -methylamine;

(1α, 3β, 4β) C- [3,4-dimethyl-1- (2-oxo-2,3-dihydro-2λ ^4- [1,2,3,5] oxathiadiazol- ⁴ -yl Methyl) -cyclopentyl] -methylamine;

(S) C- [3,3-dimethyl-1- (2-oxo-2,3-dihydro-2λ ^4- [1,2,3,5] oxathiadiazol- ⁴ -ylmethyl) -cyclo Pentyl] -methylamine;

(R) C- [3,3-dimethyl-1- (2-oxo-2,3-dihydro-2λ ^4- [1,2,3,5] oxathiadiazol- ⁴ -ylmethyl) -cyclo Pentyl] -methylamine;

C- [3,3-dimethyl-1- (2-oxo-2,3-dihydro-2λ ^4- [1,2,3,5] oxathiadiazol- ⁴ -ylmethyl) -cyclobutyl]- Methylamine;

(1-aminomethyl-cyclohexyl) -methanesulfonamide;

(1R-trans) (1-aminomethyl-3-methyl-cyclohexyl) -methanesulfonamide;

(Trans) (1-aminomethyl-3,4-dimethyl-cyclopentyl) -methanesulfonamide;

(1S-trans) (1-aminomethyl-3-methyl-cyclopentyl) -methanesulfonamide;

(1R-cis) (1-aminomethyl-3-methyl-cyclopentyl) -methanesulfonamide;

(1R-trans) (1-Aminomethyl-3-methyl-cyclopentyl) -methanesulfonamide;

(1S-cis) (1-aminomethyl-3-methyl-cyclopentyl) -methanesulfonamide;

(1α, 3β, 4β) (1-aminomethyl-3,4-dimethyl-cyclopentyl) -methanesulfonamide;

(1α, 3α, 4α) (1-aminomethyl-3,4-dimethyl-cyclopentyl) -methanesulfonamide;

(R) (1-aminomethyl-3,3-dimethyl-cyclopentyl) -methanesulfonamide;

(S) (1-aminomethyl-3,3-dimethyl-cyclopentyl) -methanesulfonamide;

(1-aminomethyl-3,3-dimethyl-cyclobutyl) -methanesulfonamide;

(1-aminomethyl-cyclohexyl) -methanesulfonic acid;

(1R-trans) (1-Aminomethyl-3-methyl-cyclohexyl) -methanesulfonic acid;

(Trans) (1-aminomethyl-3,4-dimethyl-cyclopentyl) -methanesulfonic acid;

(1S-trans) (1-Aminomethyl-3-methyl-cyclopentyl) -methanesulfonic acid;

(1S-cis) (1-aminomethyl-3-methyl-cyclopentyl) -methanesulfonic acid;

(1R-trans) (1-Aminomethyl-3-methyl-cyclopentyl) -methanesulfonic acid;

(1R-cis) (1-aminomethyl-3-methyl-cyclopentyl) -methanesulfonic acid;

(1α, 3β, 4β) (1-aminomethyl-3,4-dimethyl-cyclopentyl) -methanesulfonic acid;

(1α, 3α, 4α) (1-aminomethyl-3,4-dimethyl-cyclopentyl) -methanesulfonic acid;

(R) (1-Aminomethyl-3, 3-dimethyl-cyclopentyl) -methanesulfonic acid;

(S) (1-Aminomethyl-3, 3-dimethyl-cyclopentyl) -methanesulfonic acid;

(1-aminomethyl-3,3-dimethyl-cyclobutyl) -methanesulfonic acid;

(1-aminomethyl-cyclopentylmethyl) -phosphonic acid;

2- (1-aminomethyl-cyclopentyl) -N-hydroxy-acetamide;

N- [2- (1-Aminomethyl-cyclopentyl) -ethyl] -methanesulfonamide;

3- (1-aminomethyl-cyclopentylmethyl) -4H- [1,2,4] oxadiazol-5-one;

3- (1-aminomethyl-cyclopentylmethyl) -4H- [1,2,4] oxadiazole-5-thione;

C- [1- (1H-tetrazol-5-ylmethyl) -cyclopentyl] -methylamine;

N- [2- (1-Aminomethyl-cyclopentyl) -ethyl] -C, C, C- trifluoro- methanesulfonamide;

3- (1-aminomethyl-cyclopentylmethyl) -4H- [1,2,4] thiadiazol-5-one;

C- [1- (2-oxo-2,3-dihydro-2λ ^4- [1,2,3,5] oxathiadiazol- ⁴ -ylmethyl) -cyclopentyl] -methylamine;

(1-aminomethyl-cyclopentyl) -methanesulfonamide;

(1-aminomethyl-cyclopentyl) -methanesulfonic acid;

(9-aminomethyl-bicyclo [3.3.1] non-9-ylmethyl) -phosphonic acid;

2- (9-aminomethyl-bicyclo [3.3.1] non-9-yl) -N-hydroxy-acetamide;

N- [2- (9-Aminomethyl-bicyclo [3.3.1] non-9-yl) -ethyl] -methanesulfonamide;

3- (9-aminomethyl-bicyclo [3.3.1] non-9-ylmethyl) -4H- [1,2,4] oxadiazol-5-one;

3- (9-aminomethyl-bicyclo [3.3.1] non-9-ylmethyl) -4H- [1,2,4] oxadiazole5-thione;

C- [9- (1H-tetrazol-5-ylmethyl) -bicyclo [3.3.1] non-9-yl] -methylamine;

N- [2- (9-Aminomethyl-bicyclo [3.3.1] non-9-yl) -ethyl] -C, C, C- trifluoro- methanesulfonamide;

3- (9-aminomethyl-bicyclo [3.3.1] non-9-ylmethyl) -4H- [1,2,4] thiadiazol-5-one;

C- [9- (2-oxo-2,3-dihydro-2λ ^4- [1,2,3,5] oxathiadiazol- ⁴ -ylmethyl) -bicyclo [3.3.1] non-9 -Yl] -methylamine;

(9-aminomethyl-bicyclo [3.3.1] non-9-yl) -methanesulfonamide;

(9-aminomethyl-bicyclo [3.3.1] non-9-yl) -methanesulfonic acid;

(2-aminomethyl-adamantan-2-ylmethyl) -phosphonic acid;

2- (2-aminomethyl-adamantan-2-yl) -N-hydroxy-acetamide;

N- [2- (2-Aminomethyl-adamantan-2-yl) -ethyl] -methanesulfonamide;

3- (2-aminomethyl-adamantan-2-ylmethyl) -4H- [1,2,4] oxadiazol-5-one;

3- (2-aminomethyl-adamantan-2-ylmethyl) -4H- [1,2,4] oxadiazole-5-thione;

C- [2- (1H-tetrazol-5-ylmethyl) -adamantan-2-yl] -methylamine;

N- [2- (2-aminomethyl-adamantan-2-yl) -ethyl] -C, C, C-trifluoro-methanesulfonamide;

3- (2-aminomethyl-adamantan-2-ylmethyl) -4H- [1,2,4] thiadiazol-5-one;

C- [2- (2-oxo-2,3-dihydro-2λ ^4- [1,2,3,5] oxathiadiazol- ⁴ -ylmethyl) -adamantan-2-yl] -methyl Amines;

(2-aminomethyl-adamantan-2-yl) -methanesulfonamide;

(2-aminomethyl-adamantan-2-yl) -methanesulfonic acid;

(1-aminomethyl-cycloheptylmethyl) -phosphonic acid;

2- (1-aminomethyl-cycloheptyl) -N-hydroxy-acetamide;

N- [2- (1-Aminomethyl-cycloheptyl) -ethyl] -methanesulfonamide;

3- (1-aminomethyl-cycloheptylmethyl) -4H- [1,2,4] oxadiazole-5-thione;

N- [2- (1-Aminomethyl-cycloheptyl) -ethyl] -C, C, C- trifluoro- methanesulfonamide;

C- [1- (2-oxo-2,3-dihydro-2λ ^4- [1,2,3,5] oxathiadiazol- ⁴ -ylmethyl) -cycloheptyl] -methylamine;

(1-aminomethyl-cycloheptyl) -methanesulfonamide and

(1-Aminomethyl-cycloheptyl) -methanesulfonic acid

Use a compound of formula III, IIIC, IIIF, IIIG or IIIH selected from

Another preferred embodiment of the process of the invention uses a compound of formula III, IIIC, IIIF, IIIG or IIIH, wherein the preferred compound is a sulfonamide wherein R is selected from -NHSO ₂ R ¹⁵ or -S0 ₂ NHR ¹⁵ , R ¹⁵ is straight or branched alkyl or trifluoromethyl.

Another preferred embodiment of the process of the invention uses a compound of formula III, IIIC, IIIF, IIIG or IIIH, wherein particularly preferred is N- [2- (1-aminomethyl-cyclohexyl) -ethyl] -methanesulfone Amide.

Another preferred embodiment of the process of the invention uses a compound of formula III, IIIC, IIIF, IIIG or IIIH, wherein the other preferred compound is that R is phosphonic acid, —PO ₃ H ₂ .

Another preferred embodiment of the process of the invention uses a compound of formula III, IIIC, IIIF, IIIG or IIIH, wherein (1-aminomethyl-cyclohexylmethyl) -phosphonic acid and (2-aminomethyl-4-methyl Pentyl) -phosphonic acid is particularly preferred.

Another preferred embodiment of the process of the invention uses a compound of formula III, IIIC, IIIF, IIIG or IIIH, wherein other preferred compounds are

, ,

Heterocycle selected from.

Another preferred embodiment of the process of the invention uses a compound of formula III, IIIC, IIIF, IIIG or IIIH, wherein C- [1- (1H-tetrazol-5-ylmethyl) cyclohexyl] -methylamine and 4-methyl-2- (1H-tetrazol-5-ylmethyl) -pentylamine is particularly preferred.

Particularly preferred embodiments of the process of the invention

m is an integer from 0 to 2;

p is an integer of 2;

R is or

A compound of formula III is used.

Also preferred are embodiments of the process of the invention wherein the formula III, IIIC, IIIF, IIIG or IIIH is 3- (1-aminomethyl-cyclohexylmethyl) -4H- [1,2,4] oxadiazole-5-one Or a pharmaceutically acceptable salt thereof.

Also preferred are embodiments of the process of the invention wherein the formulas III, IIIC, IIIF, are 3- (1-aminomethyl-cyclohexylmethyl) -4H- [1,2,4] oxadiazole-5-one hydrochloride, Compounds of IIIG or IIIH are used.

Also preferred are embodiments of the process of the invention wherein the formula III, IIIC, IIIF, IIIG or IIIH is 3- (1-aminomethyl-cycloheptylmethyl) -4H- [1,2,4] oxadiazole-5-one Or a pharmaceutically acceptable salt thereof.

Also more preferred embodiments of the process of the invention are the formulas III, IIIC, IIIF, which are 3- (1-aminomethyl-cycloheptylmethyl) -4H- [1,2,4] oxadiazole-5-one hydrochloride , Compounds of IIIG or IIIH are used.

Also preferred embodiments of the process of the invention are compounds of formula III, IIIC, IIIF, IIIG or IIIH wherein C- [1- (1H-tetrazol-5-ylmethyl) -cycloheptyl] -methylamine or a pharmaceutical thereof Use an academically acceptable salt.

Also more preferred embodiments of the process of the invention use a compound of formula III, IIIC, IIIF, IIIG or IIIH which is C- [1- (1H-tetrazol-5-ylmethyl) cycloheptyl] -methylamine .

Another preferred embodiment of the process of the invention uses an alpha 2 delta ligand, which is a compound of formula IV or a pharmaceutically acceptable salt thereof.

In the above formula,

R ¹ is hydrogen, straight or branched alkyl having 1 to 6 carbon atoms, or phenyl;

R ² represents straight or branched alkyl having 1 to 8 carbon atoms, straight or branched alkenyl having 2 to 8 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, 1 to 6 carbon atoms Alkoxy, -alkylcycloalkyl, -alkylalkoxy, -alkyl OH, -alkylphenyl, -alkylphenoxy, -phenyl or substituted phenyl;

R ¹ is straight or branched alkyl having 1 to 6 carbon atoms or phenyl when R ² is methyl.

Preferred embodiments of the process of the invention use compounds of formula IV, wherein R ¹ is hydrogen and R ² is alkyl.

Another preferred embodiment of the process of the invention uses a compound of formula IV wherein R ¹ is methyl and R ² is alkyl.

In addition, another preferred embodiment of the process of the invention uses a compound of formula IV wherein R ¹ is methyl and R ² is methyl or ethyl.

Particularly preferred embodiments of the method of the invention

3-Aminomethyl-5-methylheptanoic acid;

3-Aminomethyl-5-methyl-octanoic acid;

3-Aminomethyl-5-methyl-nonanoic acid;

3-Aminomethyl-5-methyl-decanoic acid;

3-Aminomethyl-5-methyl-undecanoic acid;

3-Aminomethyl-5-methyl-dodecanoic acid;

3-Aminomethyl-5-methyl-tridecanoic acid;

3-Aminomethyl-5-cyclopropyl-hexanoic acid;

3-Aminomethyl-5-cyclobutyl-hexanoic acid;

3-Aminomethyl-5-cyclopentyl-hexanoic acid;

3-Aminomethyl-5-cyclohexyl-hexanoic acid;

3-Aminomethyl-5-trifluoromethyl-hexanoic acid;

3-Aminomethyl-5-phenyl-hexanoic acid;

3-Aminomethyl-5- (2-chlorophenyl) -hexanoic acid;

3-Aminomethyl-5- (3-chlorophenyl) -hexanoic acid;

3-Aminomethyl-5- (4-chlorophenyl) -hexanoic acid;

3-Aminomethyl-5- (2-methoxyphenyl) -hexanoic acid;

3-Aminomethyl-5- (3-methoxyphenyl) -hexanoic acid;

3-Aminomethyl-5- (4-methoxyphenyl) -hexanoic acid and

3-Aminomethyl-5- (phenylmethyl) -hexanoic acid

A compound of formula IV selected from is used.

Another particularly preferred embodiment of the method of the invention is

(3R, 4S) -3-Aminomethyl-4, 5-dimethyl-hexanoic acid;

3-Aminomethyl-4, 5-dimethyl-hexanoic acid;

(3R, 4S) -3-Aminomethyl-4, 5-dimethyl-hexanoic acid MP;

(3S, 4S) -3-Aminomethyl-4, 5-dimethyl-hexanoic acid;

(3R, 4R) -3-Aminomethyl-4, 5-dimethyl-hexanoic acid MP;

3-Aminomethyl-4-isopropyl-hexanoic acid;

3-Aminomethyl-4-isopropyl-heptanoic acid;

3-Aminomethyl-4-isopropyl-octanoic acid;

3-Aminomethyl-4-isopropyl-nonanoic acid;

3-Aminomethyl-4-isopropyl-decanoic acid and

3-Aminomethyl-4-phenyl-5-methyl-hexanoic acid

A compound of formula IV selected from is used.

Another preferred embodiment of the method of the invention,

(3S, 5S) -3-Aminomethyl-5-methoxy-hexanoic acid;

(3S, 5S) -3-Aminomethyl-5-ethoxy-hexanoic acid;

(3S, 5S) -3-Aminomethyl-5-propoxy-hexanoic acid;

(3S, 5S) -3-Aminomethyl-5-isopropoxy-hexanoic acid;

(3S, 5S) -3-Aminomethyl-5-tert-butoxy-hexanoic acid;

(3S, 5S) -3-Aminomethyl-5-fluoromethoxy-hexanoic acid;

(3S, 5S) -3-Aminomethyl-5- (2-fluoro-ethoxy) -hexanoic acid;

(3S, 5S) -3-Aminomethyl-5- (3, 3, 3-trifluoro-propoxy) -hexanoic acid;

(3S, 5S) -3-Aminomethyl-5-phenoxy-hexanoic acid;

(3S, 5S) -3-Aminomethyl-5- (4-chloro-phenoxy) -hexanoic acid;

(3S, 5S) -3-Aminomethyl-5- (3-chloro-phenoxy) -hexanoic acid;

(3S, 5S) -3-Aminomethyl-5- (2-chloro-phenoxy) -hexanoic acid;

(3S, 5S) -3-Aminomethyl-5- (4-fluoro-phenoxy) -hexanoic acid;

(3S, 5S) -3-Aminomethyl-5- (3-fluoro-phenoxy) -hexanoic acid;

(3S, 5S) -3-Aminomethyl-5- (2-fluoro-phenoxy) -hexanoic acid;

(3S, 5S) -3-Aminomethyl-5- (4-methoxy-phenoxy) -hexanoic acid;

(3S, 5S) -3-Aminomethyl-5- (3-methoxy-phenoxy) -hexanoic acid;

(3S, 5S) -3-Aminomethyl-5- (2-methoxy-phenoxy) -hexanoic acid;

(3S, 5S) -3-Aminomethyl-5- (4-nitro-phenoxy) -hexanoic acid;

(3S, 5S) -3-Aminomethyl-5- (3-nitro-phenoxy) -hexanoic acid;

(3S, 5S) -3-Aminomethyl-5- (2-nitro-phenoxy) -hexanoic acid;

(3S, 5S) -3-Aminomethyl-6-hydroxy-5-methyl-hexanoic acid;

(3S, 5S) -3-Aminomethyl-6-methoxy-5-methyl-hexanoic acid;

(3S, 5S) -3-Aminomethyl-6-ethoxy-5-methyl-hexanoic acid;

(3S, 5S) -3-Aminomethyl-5-methyl-6-propoxy-hexanoic acid;

(3S, 5S) -3-Aminomethyl-6-isopropoxy-5-methyl-hexanoic acid;

(3S, 5S) -3-Aminomethyl-6-tert-butoxy-5-methyl-hexanoic acid;

(3S, 5S) -3-Aminomethyl-6-fluoromethoxy-5-methyl-hexanoic acid;

(3S, 5S) -3-Aminomethyl-6- (2-fluoro-ethoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-Aminomethyl-5-methyl-6- (3, 3, 3-trifluoro-propoxy) -hexanoic acid;

(3S, 5S) -3-Aminomethyl-5-methyl-6-phenoxy-hexanoic acid;

(3S, 5S) -3-Aminomethyl-6- (4-chloro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-Aminomethyl-6- (3-chloro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-Aminomethyl-6- (2-chloro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-Aminomethyl-6- (4-fluoro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-Aminomethyl-6- (3-fluoro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-Aminomethyl-6- (2-fluoro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-Aminomethyl-6- (4-methoxy-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-Aminomethyl-6- (3-methoxy-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-Aminomethyl-6- (2-methoxy-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-Aminomethyl-5-methyl-6- (4-trifluoromethyl-phenoxy) -hexanoic acid;

(3S, 5S) -3-Aminomethyl-5-methyl-6- (3-trifluoromethyl-phenoxy) -hexanoic acid;

(3S, SS) -3-Aminomethyl-5-methyl-6- (2-trifluoromethyl-phenoxy) -hexanoic acid;

(3S, SS) -3-Aminomethyl-5-methyl6- (4-nitro-phenoxy) -hexanoic acid;

(3S, SS) -3-Aminomethyl-5-methyl 6- (3-nitro-phenoxy) -hexanoic acid;

(3S, 5S) -3-Aminomethyl-5-methyl6- (2-nitro-phenoxy) -hexanoic acid;

(3S, 5S) -3-Aminomethyl-6-benzyloxy-5-methyl-hexanoic acid;

(3S, 5S) -3-Aminomethyl-7-hydroxy-5-methyl-heptanoic acid;

(3S, 5S) -3-Aminomethyl-7-methoxy-5-methyl-heptanoic acid;

(3S, 5S) -3-Aminomethyl-7-ethoxy-5-methyl-heptanoic acid;

(3S, 5S) -3-Aminomethyl-5-methyl-7-propoxy-heptanoic acid;

(3S, 5S) -3-Aminomethyl-7-isopropoxy-5-methyl-heptanoic acid;

(3S, 5S) -3-Aminomethyl-7-tert-butoxy-5-methyl-heptanoic acid;

(3S, 5S) -3-Aminomethyl-7-fluoromethoxy-5-methyl-heptanoic acid;

(3S, 5S) -3-Aminomethyl-7- (2-fluoro-ethoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-Aminomethyl-5-methyl-7- (3, 3, 3-trifluoro-propoxy) -heptanoic acid;

(3S, 5S) -3-Aminomethyl-7-benzyloxy-5-methyl-heptanoic acid;

(3S, 5S) -3-Aminomethyl-5-methyl-7-phenoxy-heptanoic acid;

(3S, 5S) -3-Aminomethyl-7- (4-chloro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-Aminomethyl-7- (3-chloro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-Aminomethyl-7- (2-chloro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-Aminomethyl-7- (4-fluoro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-Aminomethyl-7- (3-fluoro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-Aminomethyl-7- (2-fluoro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-Aminomethyl-7- (4-methoxy-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-Aminomethyl-7- (3-methoxy-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-Aminomethyl-7- (2-methoxy-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-Aminomethyl-5-methyl-7- (4-trifluoromethyl-phenoxy) -heptanoic acid;

(3S, 5S) -3-Aminomethyl-5-methyl-7- (3-trifluoromethyl-phenoxy) -heptanoic acid;

(3S, 5S) -3-Aminomethyl-5-methyl-7- (2-trifluoromethyl-phenoxy) -heptanoic acid;

(3S, 5S) -3-Aminomethyl-5-methyl-7- (4-nitro-phenoxy) -heptanoic acid;

(3S, 5S) -3-Aminomethyl-5-methyl-7- (3-nitro-phenoxy) -heptanoic acid;

(3S, 5S) -3-Aminomethyl-5-methyl-7- (2-nitro-phenoxy) -heptanoic acid;

(3S, 5S) -3-Aminomethyl-5-methyl-6-phenyl-hexanoic acid;

(3S, 5S) -3-Aminomethyl-6- (4-chloro-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-Aminomethyl-6- (3-chloro-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-Aminomethyl-6- (2-chloro-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-Aminomethyl-6- (4-methoxy-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-Aminomethyl-6- (3-methoxy-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-Aminomethyl-6- (2-methoxy-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-Aminomethyl-6- (4-fluoro-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-Aminomethyl-6- (3-fluoro-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-Aminomethyl-6- (2-fluoro-phenyl) -5-methyl-hexanoic acid;

(3S, 5R) -3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid;

(3S, 5R) -3-Aminomethyl-7- (4-chloro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-Aminomethyl-7- (3-chloro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-Aminomethyl-7- (2-chloro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-Aminomethyl-7- (4-methoxy-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-Aminomethyl-7- (3-methoxy-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-Aminomethyl-7- (2-methoxy-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-Aminomethyl-7- (4-fluoro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-Aminomethyl-7- (3-fluoro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-Aminomethyl-7- (2-fluoro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-Aminomethyl-5-methyl-oct-7-enoic acid;

(3S, 5R) -3-Aminomethyl-5-methyl-non-8-enoic acid;

(E)-(3S, 5S) -3-Aminomethyl-5-methyl-oct-6-enoic acid;

(Z)-(3S, 5S) -3-Aminomethyl-5-methyl-oct-6-enoic acid;

(Z)-(3S, 5S) -3-Aminomethyl-5-methyl-non-6-enoic acid;

(E)-(3S, 5S) -3-Aminomethyl-5-methyl-non-6-enoic acid;

(E)-(3S, 5R) -3-Aminomethyl-5-methyl-non-7-enoic acid;

(Z)-(3S, 5R) -3-Aminomethyl-5-methyl-non-7-enoic acid;

(Z)-(3S, 5R) -3-Aminomethyl-5-methyl-dec-7-enoic acid;

(E)-(3S, 5R) -3-Aminomethyl-5-methyl-undec-7-enoic acid;

(3S, 5S) -3-Aminomethyl-5, 6, 6-trimethyl-heptanoic acid;

(3S, 5S) -3-Aminomethyl-5, 6-dimethyl-heptanoic acid;

(3S, 5S) -3-Aminomethyl-5-cyclopropyl-hexanoic acid;

(3S, 5S) -3-Aminomethyl-5-cyclobutyl-hexanoic acid;

(3S, 5S) -3-Aminomethyl-5-cyclopentyl-hexanoic acid; And

(3S, 5S) -3-Aminomethyl-5-cyclohexyl-hexanoic acid

A compound of formula IV selected from is used.

In addition, another more preferred embodiment of the method of the present invention,

(3S, 5R) -3-Aminomethyl-5-methyl-heptanoic acid;

(3S, 5R) -3-Aminomethyl-5-methyl-octanoic acid;

(3S, 5R) -3-Aminomethyl-5-methyl-nonanoic acid;

(3S, 5R) -3-Aminomethyl-5-methyl-decanoic acid;

(3S, 5R) -3-Aminomethyl-5-methyl-undecanoic acid;

(3S, 5R) -3-Aminomethyl-5-methyl-dodecanoic acid;

(3S, 5R) -3-Aminomethyl-5, 9-dimethyl-decanoic acid;

(3S, 5R) -3-Aminomethyl-5, 7-dimethyl-octanoic acid;

(3S, 5R) -3-Aminomethyl-5, 8-dimethyl-nonanoic acid;

(3S, 5R) -3-Aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;

(3S, 5R) -3-Aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;

(3S, 5R) -3-Aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;

(3S, 5R) -3-Aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;

(3S, 5R) -3-Aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;

(3S, 5R) -3-Aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;

(3S, 5R) -3-Aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;

(3S, 5R) -3-Aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;

(3S, 5R) -3-Aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;

(3S, 5R) -3-Aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;

(3S, 5R) -3-Aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;

(3S, 5R) -3-Aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;

(3S, 5S) -3-Aminomethyl-6-fluoro-5-methyl-hexanoic acid;

(3S, 5S) -3-Aminomethyl-7-fluoro-5-methyl-heptanoic acid;

(3S, 5R) -3-Aminomethyl-8-fluoro-5-methyl-octanoic acid;

(3S, 5R) -3-Aminomethyl-9-fluoro-5-methyl-nonanoic acid;

(3S, 5S) -3-Aminomethyl-7, 7, 7-trifluoro-5-methyl-heptanoic acid;

(3S, 5R) -3-Aminomethyl-8, 8, 8-trifluoro-5-methyl-octanoic acid;

(3S, 5R) -3-Aminomethyl-5-methyl-8-phenyl-octanoic acid;

(3S, 5S) -3-Aminomethyl-5-methyl-6-phenyl-hexanoic acid and

(3S, 5R) -3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid

A compound of formula IV selected from is used.

Another preferred embodiment of the process of the invention uses an alpha 2 delta ligand, which is a compound of formula IXA or IXB or a pharmaceutically acceptable salt thereof.

In the above formula,

n is an integer from 0 to 2;

R is sulfonamide, amide, phosphonic acid, heterocycle, sulfonic acid or hydroxamic acid;

A is hydrogen or methyl;

B is

Straight or branched alkyl having 1 to 11 carbon atoms, or

-(CH ₂ ) _1-4 -Y- (CH ₂ ) _0-4 -phenyl, wherein Y is -0-, -S-, -NR ' ₃ , and R' ₃ represents 1 to 6 carbon atoms Alkyl having 3 to 8 carbon atoms, or 1 to 3 substituents, unsubstituted or independently selected from alkyl, alkoxy, halogen, hydroxy, carboxy, carboalkoxy, trifluoromethyl and nitro, respectively Benzyl or phenyl which may be substituted.

A more preferred embodiment of the method of the invention is a compound of Formula 1A, wherein R is a sulfonamide selected from -NHSO ₂ R ¹⁵ and -S0 ₂ NHR ¹⁵ , wherein R ¹⁵ is straight or branched alkyl or trifluoromethyl Alpha 2 delta ligand, a compound of 1B, is used.

Particularly preferred embodiments of the process of the invention use a compound of formula IXA or IXB selected from:

4-methyl-2- (1H-tetrazol-5-ylmethyl) -pentylamine;

3- (2-aminomethyl-4-methyl-pentyl) -4H- [1,2,4] oxadiazole-5-thione, HCl;

(2-Aminomethyl-4-methyl-pentyl) -phosphonic acid;

3- (3-amino-2-cyclopentyl-propyl) -4H- [1,2,4] oxadiazol-5-one;

3- (3-amino-2-cyclopentyl-propyl) -4H- [1,2,4] thiadiazol-5-one;

2-cyclopentyl-3- (2-oxo-2,3-dihydro-2λ ^4- [1,2,3,5] oxathiadiazol- ⁴ -yl) -propylamine;

3- (3-amino-2-cyclobutyl-propyl) -4H- [1,2,4] oxadiazol-5-one;

3- (3-amino-2-cyclobutyl-propyl) -4H- [1,2,4] thiadiazol-5-one and

2-cyclobutyl-3- (2-oxo-2,3-dihydro-2λ ^4- [1,2,3,5] oxathiadiazol- ⁴ -yl) -propylamine.

Another preferred embodiment of the process of the invention uses a compound of formula IXA or IXB wherein R is phosphonic acid, -PO ₃ H ₂ .

Another preferred embodiment of the process of the invention is that R is

, ,

Compounds of formula IXA or IXB are used.

R is

or

Further preferred are embodiments of the process of the invention using the compound of formula IXA or IXB.

Of the present invention using a compound of formula IXA or IXB or a pharmaceutically acceptable salt thereof that is 3- (2-aminomethyl-4-methyl-pentyl) -4H- [1,3,4] oxadiazol-5-one Embodiments of the method are even more preferred.

Embodiments of the process of the invention using a compound of formula IXA or IXB which is 3- (2-aminomethyl-4-methyl-pentyl) -4H- [1,2,4] oxadiazole-5-one hydrochloride Is even more preferred.

Another embodiment uses an alpha 2 delta ligand, which is a compound of Formula V, VI, VII, or VIII or a pharmaceutically acceptable salt thereof.

In the above formula,

n is an integer from 1 to 4, each having a stereogenic center, which can be independently R or S.

Preferred embodiments of the process of the invention use compounds of formula V, VI, VII, or VIII, wherein n is an integer from 2 to 4.

Another preferred embodiment of the process of the invention uses a compound of formula V.

Even more preferred embodiments of the process of the invention use a compound of formula V, VI, VII, or VIII selected from:

(1α, 6α, 8β) (2-aminomethyl-octahydro-inden-2-yl) -acetic acid;

(2-aminomethyl-octahydro-inden-2-yl) -acetic acid;

(2-aminomethyl-octahydro-pentaren-2-yl) -acetic acid;

(2-aminomethyl-octahydro-pentaren-2-yl) -acetic acid;

(3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid;

(3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid and

(2-Aminomethyl-octahydro-inden-2-yl) -acetic acid.

Furthermore, another preferred embodiment of the method of the present invention uses a compound of formula V, VI, VII, or VIII selected from:

(1α, 5β) (3-aminomethyl-bicyclo [3.1.0] hex-3-yl) -acetic acid,

(1α, 5β) (3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid,

(1α, 5β) (2-aminomethyl-octahydro-pentaren-2-yl) -acetic acid,

(1α, 6β) (2-aminomethyl-octahydro-inden-2-yl) -acetic acid,

(1α, 7β) (2-aminomethyl-decahydro-azulen-2-yl) -acetic acid,

(1α, 5β) (3-aminomethyl-bicyclo [3.1.0] hex-3-yl) -acetic acid,

(1α, 5β) (3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid,

(1α, 5β) (2-aminomethyl-octahydro-pentaren-2-yl) -acetic acid,

(1α, 6β) (2-aminomethyl-octahydro-inden-2-yl) -acetic acid,

(1α, 7β) (2-aminomethyl-decahydro-azulen-2-yl) -acetic acid,

(1α, 3α, 5α) (3-aminomethyl-bicyclo [3.1.0] hex-3-yl) -acetic acid,

(1α, 3α, 5α) (2-aminomethyl-octahydro-pentaren-2-yl) -acetic acid,

(1α, 6α, 8α) (2-aminomethyl-octahydro-inden-2-yl) -acetic acid,

(1α, 7α, 9α) (2-aminomethyl-decahydro-azulen-2-yl) -acetic acid,

(1α, 3β, 5α) (3-aminomethyl-bicyclo [3.1.0] hex-3-yl) -acetic acid,

(1α, 3β, 5α) (3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid,

(1α, 3β, 5α) (2-aminomethyl-octahydro-pentaren-2-yl) -acetic acid,

(1α, 6α, 8β) (2-aminomethyl-octahydro-inden-2-yl) -acetic acid,

(1α, 7α, 9β) (2-aminomethyl-decahydro-azulen-2-yl) -acetic acid,

((1R, 3R, 6R) -3-Aminomethyl-bicyclo [4.1.0] hept-3-yl) -acetic acid,

((1R, 3S, 6R) -3-Aminomethyl-bicyclo [4.1.0] hept-3-yl) -acetic acid,

((1S, 3S, 6S) -3-Aminomethyl-bicyclo [4.1.0] hept-3-yl) -acetic acid,

((1S, 3R, 6S) -3-Aminomethyl-bicyclo [4.1.0] hept-3-yl) -acetic acid,

((1R, 3R, 6S) -3-Aminomethyl-bicyclo [4.2.0] oct-3-yl) -acetic acid,

((1R, 3S, 6S) -3-Aminomethyl-bicyclo [4.2.0] oct-3-yl) -acetic acid,

((1S, 3S, 6R) -3-Aminomethyl-bicyclo [4.2.0] oct-3-yl) -acetic acid,

((1S, 3R, 6R) -3-Aminomethyl-bicyclo [4.2.0] oct-3-yl) -acetic acid,

((3αR, 5R, 7αS) -5-aminomethyl-octahydro-inden-5-yl) -acetic acid,

((3αR, 5S, 7αS) -5-aminomethyl-octahydro-inden-5-yl) -acetic acid,

((3αS, 5S, 7αR) -5-aminomethyl-octahydro-inden-5-yl) -acetic acid,

((3αS, 5R, 7αR) -5-aminomethyl-octahydro-inden-5-yl) -acetic acid,

((2R, 4αS, 8αR) -2-aminomethyl-decahydro-naphthalen-2-yl) -acetic acid,

((2S, 4αS, 8αR) -2-aminomethyl-decahydro-naphthalen-2-yl) -acetic acid,

((2S, 4αR, 8αS) -2-aminomethyl-decahydro-naphthalen-2-yl) -acetic acid,

((2R, 4αR, 8αS) -2-aminomethyl-decahydro-naphthalen-2-yl) -acetic acid,

((2R, 4αS, 9αR) -2-aminomethyl-decahydro-benzocyclohepten-2-yl) -acetic acid,

((2S, 4αS, 9αR) -2-aminomethyl-decahydro-benzocyclohepten-2-yl) -acetic acid,

((2S, 4αR, 9αS) -2-aminomethyl-decahydro-benzocyclohepten-2-yl) -acetic acid,

((2R, 4αR, 9αS) -2-aminomethyl-decahydro-benzocyclohepten-2-yl) -acetic acid,

((1R, 3R, 6S) -3-Aminomethyl-bicyclo [4.1.0] hept-3-yl) -acetic acid,

((1R, 3S, 6S) -3-Aminomethyl-bicyclo [4.1.0] hept-3-yl) -acetic acid,

((1S, 3S, 6R) -3-Aminomethyl-bicyclo [4.1.0] hept-3-yl) -acetic acid,

((1S, 3R, 6R) -3-Aminomethyl-bicyclo [4.1.0] hept-3-yl) -acetic acid,

((1R, 3R, 6R) -3-Aminomethyl-bicyclo [4.2.0] oct-3-yl) -acetic acid,

((lR, 3S, 6R) -3-Aminomethyl-bicyclo [4.2.0] oct-3-yl) -acetic acid,

((1S, 3S, 6S) -3-Aminomethyl-bicyclo [4.2.0] oct-3-yl) -acetic acid,

((1S, 3R, 6S) -3-Aminomethyl-bicyclo [4.2.0] oct-3-yl) -acetic acid,

((3αR, 5R, 7αR) -5-aminomethyl-octahydro-inden-5-yl) -acetic acid,

((3αR, 5S, 7αR) -5-aminomethyl-octahydro-inden-5-yl) -acetic acid,

((3αS, 5S, 7αS) -5-aminomethyl-octahydro-inden-5-yl) -acetic acid,

((3αS, 5R, 7αS) -5-aminomethyl-octahydro-inden-5-yl) -acetic acid,

((2R, 4αR, 8αR) -2-aminomethyl-decahydro-naphthalen-2-yl) -acetic acid,

((2S, 4αS, 8αR) -2-aminomethyl-decahydro-naphthalen-2-yl) -acetic acid,

((2S, 4αR, 8αS) -2-aminomethyl-decahydro-naphthalen-2-yl) -acetic acid,

((2R, 4αS, 8αS) -2-aminomethyl-decahydro-naphthalen-2-yl) -acetic acid,

((2R, 4αR, 9αR) -2-aminomethyl-decahydro-benzocyclohepten-2-yl) -acetic acid,

((2S, 4αR, 9αR) -2-aminomethyl-decahydro-benzocyclohepten-2-yl) -acetic acid,

((2S, 4αS, 9αS) -2-aminomethyl-decahydro-benzocyclohepten-2-yl) -acetic acid and

((2R, 4αS, 9αS) -2-Aminomethyl-decahydro-benzocyclohepten-2-yl) -acetic acid.

A more preferred embodiment of the process of the invention is alpha of formula V, VI, VII, or VHI, wherein (1α, 3α, 5α) (3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid 2 delta ligands, or pharmaceutically acceptable salts thereof, are used.

Even more preferred embodiments of the process of the invention are the formulas V, VI, VII, or (1α, 3α, 5α) (3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid hydrochloride, or Alpha2delta ligand of VIII is used.

Another preferred embodiment of the process of the invention is that the alpha 2 delta ligand used is selected from the following compounds and their pharmaceutically acceptable salts:

3- (1-aminomethyl-cyclohexylmethyl) -4H- [1,2,4] oxadiazol-5-one;

(S, S)-(1-Aminomethyl-3,4-dimethyl-cyclopentyl) -acetic acid;

(R, S) -3-Aminomethyl-5-methyl-octanoic acid;

(S, R) -3-Aminomethyl-5-methyl-octanoic acid;

(3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid;

(3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid, wherein the cyclobutyl ring is trans relative to a methylamine group, and

C- [1- (1H-tetrazol-5-ylmethyl) -cycloheptyl] -methylamine.

These compounds are described as follows or PCT patent application WO 99/21824 published May 6, 1999, PCT patent application WO 00/76958 published December 21, 2000, or PCT patent published April 26, 2001. It may be prepared according to the application WO 01/28978. These applications are hereby incorporated by reference in their entirety.

A more preferred embodiment of the process of the invention uses the hydrochloride salt of compound 3- (1-aminomethyl-cyclohexylmethyl) -4H- [1,2,4] oxadiazole-5-one.

Another preferred embodiment of the method of the invention uses the cyclic amino acid of formula (I). These are described in US Pat. No. 4,024,175 and US Pat. No. 4,087,544, all of which are incorporated herein by reference in their entirety.

Another preferred embodiment of the process of the invention uses the alpha 2 delta ligand of formula II, which compounds are described in US Pat. No. 5,563,175, which is incorporated herein by reference in its entirety.

Another preferred embodiment of the method of the invention uses an alpha 2 delta ligand of formula III, IIIC, IIIF, IIIG, or IIIH. These compounds are described in PCT patent application WO 99/31075, which is incorporated by reference in its entirety herein.

Another preferred embodiment of the process of the invention uses the alpha 2 delta ligand of formula IV described in PCT patent application WO 00/76958, which is hereby incorporated by reference in its entirety.

Other preferred alpha2delta ligands that can be used in the process of the invention are the compounds of formulas IXA and IXB described in PCT patent application WO 99/31074, which is incorporated by reference in its entirety.

PCT patent application WO01 / 28978, which is incorporated herein by reference in its entirety, describes other preferred alpha2delta ligands that can be used in preferred embodiments of the present invention. Such compounds are compounds of Formulas V, VI, VII, and VIII.

Other alpha 2delta ligands that can be used in preferred embodiments of the methods of the invention are described in PCT patent application WO 99/31057, which is incorporated by reference in its entirety herein. Such alpha 2 delta ligands are compounds of formulas XII and XIII or pharmaceutically acceptable salts thereof.

In the above formula,

n is an integer from 0 to 2;

R is sulfonamide, amide, phosphonic acid, heterocycle, sulfonic acid or hydroxamic acid;

X is —0-, —S—, —S (O) —, —S (O) ₂ — or NR ′ ₁ , wherein R ′ ₁ is hydrogen, straight or branched alkyl having 1 to 6 carbon atoms , Benzyl, -C (O) R ' ₂ , wherein R' ₂ is straight or branched alkyl, benzyl or phenyl having 1 to 6 carbon atoms, or -CO ₂ R ' ₃ , wherein R' ₃ Is straight or branched alkyl having 1 to 6 carbon atoms, or benzyl, wherein the benzyl or phenyl group may be unsubstituted or substituted with 1 or 3 substituents selected from halogen, trifluoromethyl and nitro.

Other alpha 2delta ligands for use in preferred embodiments of the methods of the invention are described in PCT patent application WO 98/17627, which is incorporated by reference in its entirety herein. Such alpha 2 delta ligands are compounds of the formula: or pharmaceutically acceptable salts thereof.

In the above formula,

R is hydrogen or lower alkyl,

R ₁ is hydrogen or lower alkyl,

R ₂ is ,

Straight or branched alkyl having 7 to 11 carbon atoms or

-(CH ₂ ) _(1-4) -X- (CH ₂ ) _(0-4) -phenyl {where X is -0-, -S-, -NR _3- , where R ₃ is 1 to 6 Alkyl having 3 carbon atoms, cycloalkyl, benzyl or phenyl having 3 to 8 carbon atoms, wherein phenyl and benzyl are unsubstituted or alkyl, alkoxy, halogen, hydroxy, carboxy, carboalkoxy, trifluoro May be substituted with 1 to 3 substituents each independently selected from methyl, amino and nitro.

Other alpha 2delta ligands that can be used in preferred embodiments of the methods of the invention are described in PCT patent application WO 99/61424, which is incorporated by reference in its entirety herein. Such alpha 2 delta ligands are compounds of formulas 1, 2, 3, 4, 5, 6, 7, and 8 and pharmaceutically acceptable salts and prodrugs of these compounds.

In the above formula,

R ₁ to R ₁₀ are each independently selected from hydrogen, straight or branched alkyl having 1 to 6 carbon atoms, benzyl or phenyl;

m is an integer from 0 to 3;

n is an integer from 1 to 2;

o is an integer from 0 to 3;

p is an integer from 1 to 2;

q is an integer from 0 to 2;

r is an integer from 1 to 2;

s is an integer from 1 to 3;

t is an integer from 0 to 2;

u is an integer from 0 to 1.

Other alpha-2delta ligands that can be used in preferred embodiments of the methods of the present invention are described in US Provisional Patent Application No. 60 / 353,632, filed Jan. 31, 2002. Such alpha 2 delta ligands are compounds X, XA, XB, XI, XIA, XIB and XB-1 of the formula: Compounds of formula (X) have the following formula and pharmaceutically acceptable salts of these compounds.

In the above formula,

R ₁ is hydrogen or (C ₁ -C ₃ ) alkyl optionally substituted with 1 to 5 fluorine atoms,

R ₂ is hydrogen or (C ₁ -C ₃ ) alkyl optionally substituted with 1 to 5 fluorine atoms,

R ₃ is (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) cycloalkyl- (C ₁ -C ₃ ) alkyl, phenyl, phenyl- (C ₁ -C ₃ ) alkyl, pyridyl, pyridyl- (C ₁ -C ₃ ) alkyl, phenyl-N (H)-, or pyridyl-N (H)-, wherein each alkyl moiety is 1 to 5 fluorine atoms , Optionally substituted with 0 to 3 fluorine atoms, wherein the phenyl and the pyridyl and the phenyl- (C ₁ -C ₃ ) alkyl and the pyridyl- (C ₁ -C ₃ ) alkyl phenyl and pyridyl moieties, respectively, chloro, fluoro, amino, nitro, cyano, (C ₁ -C ₃₎ alkyl amino, one to three fluorine atoms, optionally substituted (C ₁ -C ₃₎ alkyl and 1 To 1 to 3 substituents independently selected from (C ₁ -C ₃ ) alkoxy optionally substituted with 2 to 3 fluorine atoms, preferably 0 to 2 substituents),

Provided that when R ₁ is hydrogen, R ₂ is not hydrogen.

Compounds of formula (XI) have the following formula and pharmaceutically acceptable salts of these compounds.

In the above formula, R ₁ , R ₂ and R ₃ are as defined above.

The compound of formula (XA) has the formula and pharmaceutically acceptable salts of this compound.

In the formula, R ₃ is as defined above.

Compounds of formula (XIA) have the following formulas and pharmaceutically acceptable salts of these compounds.

In the formula, R ₃ is as defined above.

The compound of formula XIB has the formula

In the above formula, R ₁ , R ₂ and R ₃ are as defined above.

The compound of formula (XB) has the formula

In the above formula, R ₁ , R ₂ and R ₃ are as defined above.

The compound of formula (XB-1) has the formula

In the formula, R ₃ is as defined above.

All U.S. quoted above. Patents and WO publications are hereby incorporated by reference in their entirety.

It should be understood that the terms "uses", "utilizes" and "empolys" may be used interchangeably in describing embodiments of the present invention.

The term "lower alkyl" refers to a straight or branched alkyl group or radical having 1 to 6 carbon atoms and is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert -Butyl, n-pentyl, n-hexyl and the like.

The term "alkyl" is not limited thereto, including methyl, ethyl, propyl, n-propyl, isopropyl, butyl, 2-butyl, tert-butyl, and octyl, unless stated otherwise straight chain of 1 to 8 carbon atoms Or a branched group. Alkyl may be unsubstituted or substituted with hydroxy or 1-3 fluorine atoms. Preferred groups are methyl and ethyl.

The term "alkenyl" refers to ethynyl, propen-1-yl, propen-2-yl, propen-3-yl, 1-hexen-3-yl, and hept-1, 3-dien-7-yl Including but not limited to, straight or branched groups having from 2 to 8 carbon atoms containing 1 or 2 or 3 double bonds.

Alkenyl may be unsubstituted or substituted with 1 to 3 fluorine atoms.

The term "cycloalkyl" refers to a cyclic group having 3 to 7 carbon atoms, including but not limited to cyclopropyl, cyclobutyl, and cycloheptyl.

Benzyl and phenyl groups may be unsubstituted or substituted with 1 to 3 groups each independently selected from halogen, in particular fluoro, alkoxy, alkyl, and NH ₂ .

"Halogen" includes fluorine, chlorine, bromine, and iodine.

The term "alkoxy" means the group -O-alkyl, wherein alkyl is as previously defined.

Sulfonamides are compounds of the formula -NHSO ₂ R ¹⁵ or -S0 ₂ NHR ¹⁵ , wherein R ¹⁵ is a straight or branched alkyl group or trifluoromethyl having 1 to 6 carbon atoms.

Amides are compounds of the formula -NHCOR ¹² , wherein R ¹² is straight or branched alkyl, benzyl and phenyl having 1 to 6 carbon atoms.

Phosphonic acid is -PO ₃ H ₂ .

Sulfonic acid is -SO ₃ H.

Hydroxamic acid to be.

The heterocycle is a bicyclic group having 1 to 2 ring groups having 1 to 6 heteroatoms selected from oxygen, nitrogen, and sulfur, a monocyclic ring having 4 to 7 ring members, and 7 to 12 ring members. Cyclic rings.

Preferred heterocycles are

, , to be.

The term alkyl is limited thereto, including methyl, ethyl, propyl, n-propyl, isopropyl, butyl, 2-butyl, tert-butyl, pentyl, hexyl, and n-hexyl, heptyl, octyl, nonyl, decyl, and undecyl And, unless stated otherwise, are straight or branched groups having 1 to 11 carbon atoms.

Cycloalkyl groups are 3 to 8 carbons and unless otherwise stated are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

Benzyl and phenyl groups may be unsubstituted or substituted with 1 to 3 substituents selected from hydroxy, carboxy, carboalkoxy, halogen, CF3, nitro, alkyl, and alkoxy. Fluorine and chlorine are preferred.

Carboalkoxy is -COOalkyl, where alkyl is as previously defined. Carbomethoxy and carboethoxy are preferred.

Detailed description of the invention

The degree of binding to the α2δ subunits is described in NS Gee et al. Chem, 1996, 271:. 5879-5776 ] may be a, measured in radioligand binding assays using the α2δ subunit derived from ^[3 H] gabapentin and pig brain tissue as described.

The ability of these compounds to treat ADHD is described by Carol A. Bauer, "Assessing ADHD and Prospective ADHD Therapeutics Using a Psychological Animal Model," Journal of the Association for Research in Otolaryngology, 2/1: 054-. 064 (2001).

All that is needed to practice the method of the present invention is to administer an alpha 2 delta ligand or a pharmaceutically acceptable salt thereof in a therapeutically effective amount for treating ADHD. The ADHD- therapeutic amount is typically about 1 to about 300 mg / kg of the subject's body weight. Typical doses are about 10 to about 5000 mg / day for normal body weight of an adult subject. In a clinical setting, regulatory bodies such as the US Food and Drug Administration (“FDA”) may require a specific therapeutically effective amount.

In determining what constitutes an effective amount or therapeutically effective amount of an alpha 2 delta ligand or a pharmaceutically acceptable salt thereof for treating ADHD in accordance with the methods of the present invention, the physician or veterinarian will typically have their experience, published medical studies, subjects Many factors will be considered in light of the age, sex, weight and general condition of the mammal (ie, mammal), and the type and extent of the disease, disorder or condition being treated, and the use of other drugs by the subject, if any. Thus, the dose to be administered may be included in the above-mentioned ranges or concentrations, or may vary outside of that range, i.e., below or above that range, which may be determined by the needs of the individual subject, the depth of symptoms to be treated and It depends on the specific therapeutic agent used. Determination of the appropriate dose for a particular situation is within the skill of the medical or veterinary arts. Typically, treatment can begin with a small dose that is an alpha 2 delta ligand below the optimum for a particular subject. Thereafter, the dose may be increased little by little until the optimum effect is reached at that condition. For convenience, the total daily dose may be divided into several portions and administered throughout the day as needed.

Pharmaceutical compositions of alpha2delta ligands or pharmaceutically acceptable salts thereof may be prepared by formulating a dosage unit form of the active compound with a pharmaceutical carrier. Some examples of dosage unit forms are tablets, capsules, pills, powders, aqueous and non-aqueous oral solutions and suspensions, and parenteral solutions, packaged in a container containing one or more dosage units and divided into individual doses. .

Some examples of suitable pharmaceutical carriers, including pharmaceutical diluents, include gelatin capsules; Sugars such as lactose and sucrose; Starch such as corn starch and potato starch; Cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose and cellulose acetate phthalate; gelatin; Talc; Stearic acid; Magnesium stearate; Vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and theobroma oil; Propylene glycol, glycerin; Sorbitol; Polyethylene glycol; water; Baby; Alginic acid; Isotonic saline and phosphate buffer solutions; And other suitable ingredients conventionally used in pharmaceutical formulations.

The composition used in the present invention may also contain other ingredients such as colorants, perfumes and / or preservatives. The materials are typically used in relatively small amounts if present. If necessary, the composition may also contain other therapeutic agents commonly used to treat ADHD. Furthermore, if necessary, the composition may also contain other therapeutic agents commonly used in the treatment of secondary symptoms, such as depression or anxiety, which may or may not accompany ADHD. For example, the composition may comprise aspirin, naprosin, or similar anti-inflammatory analgesics.

The percentage of active ingredient in the composition may vary within wide ranges, but for practical purposes it is preferably present at a concentration of at least 10% in the solid composition and at least 2% in the primary liquid composition. The most satisfactory compositions are those with a much higher proportion of active ingredient, for example up to about 95%.

Preferred routes of administration of alpha 2 delta ligands or pharmaceutically acceptable salts thereof are oral or parenteral. For example, a useful intravenous dose is 5-50 mg and a useful oral dose is 20-800 mg.

Alpha 2delta ligands, or pharmaceutically acceptable salts thereof, may be administered in any form. Preferably, administration is in unit dosage form. In addition, unit dosage forms of alpha2delta ligands, or pharmaceutically acceptable salts thereof, that may be used in the present invention may include other compounds useful for treating diseases that can cause ADHD.

The methods of the present invention are useful in human and veterinary medicaments for treating or preventing ADHD in mammals.

Some compounds used in the methods of the present invention may also form pharmaceutically acceptable salts, including but not limited to acid additions and / or base salts. Acid addition salts are formed from basic compounds, while base addition salts are formed from acidic compounds. All such forms belong to the compound domain useful in the methods of the invention.

Pharmaceutically acceptable acid addition salts of basic compounds useful in the process of the invention are non-toxic salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like, as well as Non-toxic salts derived from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like. Thus, the salts may be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromide, iodides, Acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suverate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methyl Benzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate and the like. In addition, salts of amino acids such as alginate and the like gluconate, galacturonate (see, eg, Berg SM et al., “Pharmaceutical Salts,” J. of Pharma. Sci., 1977; 66: 1 ] Is considered.

Acid addition salts of basic compounds useful in the process of the present invention are prepared by contacting a compound in the free base form with a sufficient amount of a predetermined acid to produce a non-toxic salt in a conventional manner. The free base form of the compound can be regenerated by contacting the acid addition salt thus formed with a base and isolating the compound in free base form in a conventional manner. Compounds in the free base form prepared according to the process of the present invention differ somewhat from their respective acid addition salt forms in certain physical properties, such as solubility, crystal structure, hygroscopicity, etc. And their respective acid addition salt forms meet the purpose of the present invention.

Pharmaceutically acceptable base addition salts of acidic compounds useful in the process of the invention can be prepared by contacting the compounds in free acid form with a nontoxic metal cation, for example an alkali or alkaline earth metal cation, or an amine, in particular an organic amine. have. Suitable metal cations include, for example, sodium cations (Na ⁺ ), potassium cations (K ⁺ ), magnesium cations (Mg ²⁺ ), calcium cations (Ca ²⁺ ), and the like. Suitable amines are, for example, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine and procaine (e.g. See Berge, 1977).

Base addition salts of acidic compounds useful in the process of the present invention can be prepared by contacting the compound in free acid form with a sufficient amount of the desired base to produce the salt in a conventional manner. Compounds in free acid form can be regenerated by contacting the salt form so formed with an acid and isolating the compound which is the free acid in a conventional manner. Compounds in free acid form useful in the process of the present invention differ somewhat from their respective salt forms in certain physical properties, such as solubility, crystal structure, hygroscopicity, etc., but in other respects salts may differ from each other for the purposes of the present invention. Is equivalent to the free acid of

Certain compounds useful in the methods of the invention may exist in solvated forms, including unsolvated forms and hydrated forms. Typically, solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be included within the scope of the present invention.

Certain compounds useful in the methods of the invention have one or more chiral centers, each of which may exist in an R or S configuration. The methods of the present invention can use any diastereoisomer, enantiomeric or epimeric form of the alpha 2delta ligand, or a pharmaceutically acceptable salt thereof, and mixtures thereof.

In addition, certain compounds useful in the methods of the present invention may exist as geometric isomers, such as the entgegen (E) and zusammen (Z) isomers of alkenyl groups. The methods of the present invention may use any cis, trans, syn, anti, entgegen (E), or zimen (Z) isomer of an alpha 2 delta ligand or a pharmaceutically acceptable salt thereof, and mixtures thereof.

Certain compounds useful in the methods of the invention may exist as two or more tautomeric forms. Compounds in tautomeric forms can be replaced, for example, by enolation / de-enolation and the like. The methods of the present invention can employ any tautomeric forms of alpha 2 delta ligands or pharmaceutically acceptable salts thereof, and mixtures thereof.

The following examples illustrate pharmaceutical compositions of the present invention comprising a therapeutically effective amount of an alpha 2delta ligand of ADHD and a pharmaceutically acceptable carrier, diluent or excipient. The examples are illustrative only and are not intended to limit the invention in any respect.

Formulation Example 1

Tablet Formulation 1 :

ingredient Volume (mg) 3- (1-aminomethyl-cyclohexylmethyl) -4H- [1,2,4] oxadiazol-5-one hydrochloride 25 Lactose 50 Corn Starch (Mixed) 10 Corn Starch (paste) 10 Magnesium Stearate (1%) 5 gun 100

3- (1-aminomethyl-cyclohexylmethyl) -4H- [1,2,4] oxadiazole-5-one hydrochloride, lactose and corn starch (for mixing) were uniformly blended. Corn starch (for paste) was suspended in 200 mL of water and heated with stirring to form a paste. The paste was used to granulate the mixed powder. The wet granules were passed through a hand screen eight times and dried at 80 ° C. Dry granules were lubricated with 1% magnesium stearate and compressed into tablets. The tablets may be administered to humans 1 to 4 times a day to treat ADHD.

Formulation Example 2

Coated Tablets :

The tablets of Formulation Example 1 were coated with sucrose, potato starch, talc, tragacanth and pigments in a conventional manner.

Formulation Example 3

Injection Vials :

The pH of 500 g of gabapentin and 5 g of disodium hydrogen phosphate solution was adjusted to pH 6.5 in 3 L double-distilled water with 2 M hydrochloric acid. The solution was sterile filtered and the filtrate was placed in an injection vial lyophilized under sterile conditions and sealed aseptically. Each injection vial contains 25 mg of gabapentin.

Formulation Example 4

Suppositories :

Fuse a mixture of 25 g (1α, 3α, 5α) (3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid hydrochloride, 100 g soy lecithin, and 1400 g cocoa butter Into the mold and allowed to cool. Each suppository contains 25 mg (1α, 3α, 5α) (3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid hydrochloride.

Formulation Example 5

Solution :

1 g 3- (2-aminomethyl-4-methyl-pentyl) -4H- [1,2,4] -oxadiazol-5-one hydrochloride in 940 mL double-distilled water, 9.38 g NaH ₂ The solution was prepared from PO ₄ 12H ₂ O, 28.48 g Na ₂ HPO ₄ 12H ₂ O and 0.1 g benzalkonium chloride. The pH of the solution was adjusted to pH 6.8 with 2 M hydrochloric acid. The solution was diluted with 1.0 L of double-distilled water and sterilized by irradiation. The 25 mL volume of solution contains 25 mg of 3- (2-aminomethyl-4-methyl-pentyl) -4H- [1,2,4] -oxadiazole-5-one hydrochloride.

Formulation Example 6

Ointment :

500 mg of 3- (1-aminomethyl-cycloheptylmethyl) -4H- [1,2,4] oxadiazol-5-one hydrochloride were mixed with 99.5 g of petroleum jelly under aseptic conditions. The 5 g ointment contains 25 mg of 3- (1-aminomethyl-cycloheptylmethyl) -4H- [1,2,4] oxadiazol-5-one hydrochloride.

Formulation Example 7

Capsule :

2 kg of 3- (1-amino) such that each capsule contains 25 mg of 3- (1-aminomethyl-cyclohexylmethyl) -4H- [1,2,4] oxadiazol-5-one hydrochloride Methyl-cyclohexylmethyl) -4H- [1,2,4] oxadiazole-5-one hydrochloride was filled into hard gelatin capsules in a conventional manner.

Formulation Example 8

Ampoules :

A 2.5 kg solution of gabapentin was dissolved in 60 L of double-distilled water. The solution was sterile filtered and the filtrate was filled in ampoules. The ampoule was sterile sealed under sterile conditions. Each ampoule contains 25 mg of gabapentin.

Various embodiments are described herein describing the methods of the present invention.

Claims (15)

A method of treating ADHD in a mammal suffering from ADHD, comprising administering a therapeutically effective amount of an alpha 2 delta ligand or a pharmaceutically acceptable salt thereof to the mammal in need thereof. The compound of claim 1, wherein said alpha2delta ligand is gabapentin. The method of claim 1, wherein said alpha2delta ligand is pregabalin. The method of claim 1, wherein the alpha 2 delta ligand is selected from the following compounds and their pharmaceutically acceptable salts. R- (3)-(aminomethyl) -5-methyl-hexanoic acid, 3- (1-aminoethyl) -5-methylheptanoic acid, 3- (1-aminomethyl-cyclohexylmethyl) -4H- [1,2,4] oxadiazol-5-one, N- [2- (1-Aminomethyl-cyclohexyl) -ethyl] -methanesulfonamide, 3- (1-aminomethyl-cycloheptylmethyl) -4H- [1,2,4] oxadiazol-5-one, C- [1- (1H-tetrazol-5-ylmethyl) -cycloheptyl] -methylamine, C- [1- (1H-tetrazol-5-ylmethyl) cyclohexyl] -methylamine, 4-methyl-2- (1H-tetrazol-5-ylmethyl) -pentylamine, (1α, 3α, 5α) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid, 3- (2-aminomethyl-4-methyl-pentyl) -4H- [1,2,4] oxadiazol-5-one, and 3- (1-Aminoethyl) -5-methylhexanoic acid. According to claim 1, wherein the alpha 2 delta ligand is a compound of the formula Their pharmaceutically acceptable salts. <Formula III> <Formula IIIC> <Formula IIIF> <Formula IIIG> <Formula IIIH> In the above formula, n is an integer from 0 to 2, m is an integer from 0 to 3, R is sulfonamide, amide, phosphonic acid, heterocycle, sulfonic acid or hydroxamic acid, R ₁ to R ₁₄ are hydrogen, straight or branched alkyl having 1 to 6 carbon atoms, unsubstituted or substituted with halogen, alkyl, alkoxy, hydroxy, carboxy, carboalkoxy, trifluoromethyl and nitro Each independently selected from substituted benzyl or phenyl, A ' , , , And Bridged ring selected from here Is the bond point, Z ₁ to Z ₄ are each independently selected from hydrogen and methyl, o is an integer from 1 to 4, p is an integer from 0 to 2, Provided that when m is 2 and n is 1, R in formula 1 is not -SO ₃ H. The method of claim 1, wherein the alpha 2 delta ligand is a compound of Formula IIIa or a pharmaceutically acceptable salt thereof. In the above formula, m is an integer from 0 to 2, p is an integer of 2, R is or to be. The method of claim 1, wherein said alpha2delta ligand is a compound of Formula IV or a pharmaceutically acceptable salt thereof. <Formula IV> In the above formula, R ¹ is hydrogen, straight or branched alkyl having 1 to 6 carbon atoms, or phenyl, R ² represents straight or branched alkyl having 1 to 8 carbon atoms, straight or branched alkenyl having 2 to 8 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, 1 to 6 carbon atoms Alkoxy, -alkylcycloalkyl, -alkylalkoxy, -alkyl OH, -alkylphenyl, -alkylphenoxy, -phenyl or substituted phenyl, R ¹ is straight or branched alkyl having 1 to 6 carbon atoms or phenyl when R ² is methyl. The method of claim 1, wherein said alpha2delta ligand is a compound of Formula IXA or Formula IXB or a pharmaceutically acceptable salt thereof. <Formula IXA> <Formula IXB> In the above formula, n is an integer from 0 to 2, R is sulfonamide, amide, phosphonic acid, heterocycle, sulfonic acid or hydroxamic acid, A is hydrogen or methyl, B is , Straight or branched alkyl having 1 to 11 carbon atoms, or -(CH ₂ ) _1-4 -Y- (CH ₂ ) _0-4 -phenyl, wherein Y is -0-, -S-, -NR ' ₃ , and R' ₃ represents 1 to 6 carbon atoms Alkyl having 3 to 8 carbon atoms, or 1 to 3 substituents, unsubstituted or independently selected from alkyl, alkoxy, halogen, hydroxy, carboxy, carboalkoxy, trifluoromethyl and nitro, respectively Benzyl or phenyl which may be substituted. The method of claim 8, wherein the compound of Formula IXA or IXB is selected from: 4-methyl-2- (1H-tetrazol-5-ylmethyl) -pentylamine, 3- (2-aminomethyl-4-methyl-pentyl) -4H- [1,2,4] oxadiazole-5-thione, HCl, (2-aminomethyl-4-methyl-pentyl) -phosphonic acid, 3- (3-amino-2-cyclopentyl-propyl) -4H- [1,2,4] oxadiazol-5-one, 3- (3-amino-2-cyclopentyl-propyl) -4H- [1,2,4] thiadiazol-5-one, 2-cyclopentyl-3- (2-oxo-2,3-dihydro-2λ ^4- [1,2,3,5] oxathiadiazol- ⁴ -yl) -propylamine, 3- (3-amino-2-cyclobutyl-propyl) -4H- [1,2,4] oxadiazol-5-one, 3- (3-amino-2-cyclobutyl-propyl) -4H- [1,2,4] thiadiazol-5-one, and 2-cyclobutyl-3- (2-oxo-2,3-dihydro-2λ ^4- [1,2,3,5] oxathiadiazol- ⁴ -yl) -propylamine. The method of claim 1, wherein the alpha 2 delta ligand is a compound of Formula V, VI, VII, or VIII or a pharmaceutically acceptable salt thereof. <Formula V> <Formula VI> <Formula VII> <Formula VIII> In the above formula, n is an integer from 1 to 4, each having a stereogenic center, which can be independently R or S. The method of claim 10, wherein said alpha 2 delta ligand is selected from: (1α, 6α, 8β) (2-aminomethyl-octahydro-inden-2-yl) -acetic acid, (2-aminomethyl-octahydro-inden-2-yl) -acetic acid, (2-aminomethyl-octahydro-pentaren-2-yl) -acetic acid, (2-aminomethyl-octahydro-pentaren-2-yl) -acetic acid, (3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid, (3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid, and (2-Aminomethyl-octahydro-inden-2-yl) -acetic acid. The method of claim 1, wherein the alpha 2 delta ligand is a compound of Formula XII or XIII or a pharmaceutically acceptable salt thereof. <Formula XII> <Formula XIII> In the above formula, n is an integer from 0 to 2; R is sulfonamide, amide, phosphonic acid, heterocycle, sulfonic acid or hydroxamic acid; X is —0-, —S—, —S (O) —, —S (O) ₂ — or NR ′ ₁ , wherein R ′ ₁ is hydrogen, straight or branched alkyl having 1 to 6 carbon atoms , Benzyl, -C (O) R ' ₂ , wherein R' ₂ is straight or branched alkyl, benzyl or phenyl having 1 to 6 carbon atoms, or -CO ₂ R ' ₃ , wherein R' ₃ Is straight or branched alkyl having 1 to 6 carbon atoms, or benzyl, wherein the benzyl or phenyl group may be unsubstituted or substituted with 1 or 3 substituents selected from halogen, trifluoromethyl and nitro. The method of claim 1, wherein the alpha 2 delta ligand is a compound of formula: or a pharmaceutically acceptable salt thereof. In the above formula, R is hydrogen or lower alkyl, R ₁ is hydrogen or lower alkyl, R ₂ is , Straight or branched alkyl having 7 to 11 carbon atoms or -(CH ₂ ) _(1-4) -X- (CH ₂ ) _(0-4) -phenyl {where X is -0-, -S-, -NR _3- , where R ₃ is 1 to 6 Alkyl having 3 carbon atoms, cycloalkyl, benzyl or phenyl having 3 to 8 carbon atoms, wherein phenyl and benzyl are unsubstituted or alkyl, alkoxy, halogen, hydroxy, carboxy, carboalkoxy, trifluoro May be substituted with 1 to 3 substituents each independently selected from methyl, amino and nitro. The method of claim 1, wherein the alpha 2 delta ligand is a compound of Formula 1, 2, 3, 4, 5, 6, 7, or 8, or a pharmaceutically acceptable salt thereof, or a prodrug thereof. <Formula 1> <Formula 2> <Formula 3> <Formula 4> <Formula 5> <Formula 6> <Formula 7> <Formula 8> In the above formula, R ₁ to R ₁₀ are each independently selected from hydrogen, straight or branched alkyl having 1 to 6 carbon atoms, benzyl or phenyl, m is an integer from 0 to 3, n is an integer of 1 to 2, o is an integer from 0 to 3, p is an integer from 1 to 2, q is an integer from 0 to 2, r is an integer from 1 to 2, s is an integer of 1 to 3, t is an integer from 0 to 2, u is an integer from 0 to 1. The method of claim 1, wherein the alpha 2 delta ligand is a compound of Formula X or XI and a pharmaceutically acceptable salt of such compound. <Formula X> <Formula XI> In the above formula, R ₁ is hydrogen or (C ₁ -C ₃ ) alkyl optionally substituted with 1 to 5 fluorine atoms, R ₂ is hydrogen or (C ₁ -C ₃ ) alkyl optionally substituted with 1 to 5 fluorine atoms, R ₃ is (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) cycloalkyl- (C ₁ -C ₃ ) alkyl, phenyl, phenyl- (C ₁ -C ₃ ) alkyl, pyridyl, pyridyl- (C ₁ -C ₃ ) alkyl, phenyl-N (H)-, or pyridyl-N (H)-, wherein each alkyl moiety is 1 to 5 fluorine atoms , Optionally substituted with 0 to 3 fluorine atoms, wherein the phenyl and the pyridyl and the phenyl- (C ₁ -C ₃ ) alkyl and the pyridyl- (C ₁ -C ₃ ) alkyl phenyl and pyridyl moieties, respectively, chloro, fluoro, amino, nitro, cyano, (C ₁ -C ₃₎ alkyl amino, one to three fluorine atoms, optionally substituted (C ₁ -C ₃₎ alkyl and 1 To 1 to 3 substituents independently selected from (C ₁ -C ₃ ) alkoxy optionally substituted with 2 to 3 fluorine atoms, preferably 0 to 2 substituents), Provided that when R ₁ is hydrogen, R ₂ is not hydrogen.