WO2010057899A1 - Cycloalkyl amino carbonyl derivatives as bradykinin-b1 receptor antagonists - Google Patents

Abstract

The present invention relates to compounds of the general formula (I), in which A, R1, R2a, R2b, R3, R4 and R5 are defined as described below, to enantiomers, diastereomers, mixtures and salts thereof, in particular physiologically compatible salts thereof with organic or inorganic acids or bases possessing valuable properties, to the manufacture of said compounds, to medicines comprising the pharmacologically effective compounds, and to the manufacture and use of said pharmacologically effective compounds.

Description

 CYKLOALKYLAMINOCARBONYL DERIVATIVES AS BRADYKININ BI RECEPTOR

Antagonists

The present invention relates to compounds of general formula I.

in which A, R ¹ , R ^2a , R ^2b , R ³ , R ⁴ and R ⁵ are defined as described below, their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts with organic or inorganic acids or Bases which have valuable properties, their preparation, the medicaments containing the pharmacologically active compounds, their preparation and their use.

DETAILED DESCRIPTION OF THE INVENTION

In the general formula I mean in a first embodiment

A is a direct bond, a -CH ₂ -, -CH ₂ -CH ₂ - or a

-CH ₂ -CH ₂ -CH ₂ - group;

R ^{1 is} (a) a phenyl group which may be optionally substituted with 1, 2 or 3 R ^{1 1} radicals;

(b) a 5- or 6-membered heteroaryl group which may optionally be substituted with one or two of R ^{1 2} ;

R ^{1 1} independently

(a) halogen,

(b) d-3-alkyl which is optionally partially or fully fluorinated;

(c) -OH; -O-d-3-alkyl which is optionally partially or completely fluorinated;

(d) -NR ^{1 2 1} R ¹ - ²² , (e) -CN; R ^{1 2} independently

(a) halogen,

(b) d-3-alkyl which is optionally partially or fully fluorinated; (C) -OH, -O-Ci-3-alkyl,

(d) -NR ^{1 2 1} R ¹ - ²² ,

(e) -CN;

R ¹ - ² - ¹ , R ¹ - ² - ^{2 are} independently (a) H,

(b) C _1-3 alkyl, or together form a C _3- 7-alkylene group;

_R 2a _R 2b independently

(a) H or

(b) C _1-8 alkyl;

R ³ (a) H or

(b) Ci-6-alkyl;

R ⁴ (a) a Phenvlaruoo, 4.1 can be substituted,

(b) a 5- or 6-membered heteroaryl group which may optionally be substituted with 1, 2 or 3 R ⁴² radicals;

R ⁴ - ¹ independently

(a) halogen,

(b) d- _3- alkyl which is optionally partially or completely fluorinated; (C) -COO-R ⁴ - ¹ - ¹ , (d) -CO-R ^{4 1 2} ,

(e) -CN,

(f) -OH, -O-Ci-3-alkyl, -O-CH ₂ CF ₃ ,

(g) -NR ^{4 1 3} R ⁴ - ^{1 4} , (h) phenyl, (i) heteroaryl or

(j) a heterocyclic ring, in particular selected from

R " ^{1 1} (a) H,

(b) Ci-3-alkyl,

(c) benzyl;

_R 4.1.2 (a) .NR ^{4 1 2 1} R ⁴ - ¹ - ² - ²

(b) C _1-3 alkyl;

R ⁴ - ¹ - ³ , R ⁴ - ¹ - ⁴ independently

(a) H,

(b) C _1-3 alkyl, (C) -C (O) -Ci _-3 alkyl,

(d) -C (O) -C _3-7 cycloalkyl,

(e) benzoyl;

R ⁴ - ¹ - ² - ¹ , R ⁴ - ¹ - ² - ² independently of one another (a) H,

(b) C _1-3 alkyl,

(C) C _3-7 cycloalkyl,

(d) benzyl; or

R ⁴ - ¹ - ² - ¹ and R ⁴ - ¹ - ² - ² together with the N-atom to which they are attached, can form a 4-, 5- or 6-membered heterocyclic ring, which is additionally a further heteroatom selected from N, O and S may contain;

R ⁴ - ^{2 are} independent of each other - A -

(a) halogen,

(b) Ci-3-alkyl,

(c) d-3-alkyl which is optionally partially or fully fluorinated;

R ⁵ up to three substituents which are independently selected from

(a) Ci-3-alkyl,

(b) -OH,

as well as their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts with organic or inorganic acids or bases.

A second embodiment of the present invention consists in the compounds of the general formula I in which R ¹ , R ^2a , R ^2b , R ³ , R ⁴ and R ^{5 are defined} as mentioned above under the first embodiment, and

A is a direct bond, namely compounds of formula Ia:

as well as their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts with organic or inorganic acids or bases.

A third embodiment of the present invention consists in the compounds of the general formulas I or Ia in which A, R ^2a , R ^2b , R ³ , R ⁴ and R ^{5 are defined} as mentioned above under the first or second embodiment, and

R ^{1 is} a group selected from

means

their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts with organic or inorganic acids or bases.

A fourth embodiment of the present invention consists in the compounds of the general formula I or Ia in which A, R ¹ , R ^2a , R ^2b , R ³ and R ^{5 are defined} as mentioned above under the first, second or third embodiment and

R ^{4 is} a group selected from

means

their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts with organic or inorganic acids or bases. A fifth embodiment of the present invention consists in the compounds of the general formula I or Ia in which A, R ¹ , R ^2b , R ³ , R ⁴ and R ^{5 are defined} as mentioned above under the first, second, third or fourth embodiments and

»2a means hydrogen,

their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts with organic or inorganic acids or bases.

A sixth embodiment of the present invention consists in the compounds of the general formula I or Ia in which A, R ¹ , R ^2a , R ³ , R ⁴ and R ^{5 are defined} as mentioned above under the first embodiment, and

, 2b is hydrogen,

their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts with organic or inorganic acids or bases.

As very particularly preferred compounds of the general formula I, the following may be mentioned, for example:

1

11 12

13 14

15 16

17 18

19 20

21 22

23 24

25 26

29 30

31 32

35 36

37 38

39 40

41 42

43 44

45 46

47 48

49 50

51 52

53 54

55 56

57 58

59 60

61 62

63 64

65 66

67 68

71 72

73 74

79 80

81 82

83 84

85 86

87 88

89

their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts with organic or inorganic acids or bases.

USED TERMS AND DEFINITIONS

Unless otherwise indicated, all substituents are independent of each other. If more than one Ci to be a group, for example, _-6 alkyl groups as substituents, one could independently of each other one may represent methyl, one n-propyl and one mean te / f-butyl in the case of three substituents Ci _-6 alkyl.

In the context of this application, in the definition of possible substituents, these can also be represented in the form of a structural formula. It will, if available, an asterisk (*) in the structural formula of the substituent is understood as the point of attachment to the remainder of the molecule.

Also included in the subject matter of this invention are the compounds of the invention, including their salts, in which one or more hydrogen atoms, for example one, two, three, four or five hydrogen atoms, are replaced by deuterium.

The term "C _1-3 alkyl" (including those which are part of other groups) are alkyl groups having 1, 2 or 3 carbon atoms, branched, the term _"C-M-alkyl" and unbranched alkyl groups having 1, 2, 3 or 4 carbon atoms, by the term "C 1-6 -alkyl" branched and unbranched alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms and by the term "C _1-8 -alkyl" branched and unbranched alkyl groups with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms understood. Examples include: methyl, ethyl, n-propyl, / so-propyl, n-butyl, / so-butyl, sec-butyl, te / f-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl , n-octyl. Optionally, the abbreviations Me, Et, n-Pr, / -Pr, n-Bu, / -Bu, t-Bu, etc. are also used for the abovementioned groups. Unless otherwise stated, the definitions pentyl, hexyl, heptyl, octyl, propyl and butyl include all conceivable isomeric forms of the respective radicals. For example, propyl includes n-propyl and / so-propyl, butyl includes / so-butyl, sec-butyl and te / f-butyl.

Furthermore, the abovementioned terms also include those radicals in which each methylene group can be substituted by 1 or 2 and each methyl group by 1, 2 or 3 fluorine atoms.

The term "C _3-7 -alkylene" is understood to mean branched and unbranched alkylene groups having 3, 4, 5, 6 or 7 carbon atoms. For example: propylene, butylene, pentylene. Furthermore, the terms above also include those radicals in which each methylene group may be substituted by 1 or 2 fluorine atoms.

The term "C _3-7 -cycloalkyl" (even if they are part of other radicals) are cyclic alkyl groups having 3, 4, 5, 6 or 7 carbon atoms and by the term "C _3-6 -cycloalkyl" cyclic alkyl groups with 3 , 4, 5 or 6 carbon atoms Understood. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Unless otherwise described, the cyclic alkyl groups may be substituted with one or more groups selected from the group consisting of methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluoro, chloro, bromo and iodo.

"Halogen" in the context of the present invention is fluorine, chlorine, bromine or iodine. Unless otherwise indicated, fluorine, chlorine and bromine are preferred halogens.

The term "heterocyclic rings" is understood to mean stable 4-, 5- or 6-membered monocyclic heterocyclic ring systems which may be both saturated and monounsaturated and may carry, in addition to carbon atoms, one or two heteroatoms selected from the group consisting of Nitrogen, oxygen and sulfur. Both nitrogen and sulfur heteroatoms can optionally be oxidized. The above heterocycles may be linked via a carbon atom or via a nitrogen atom with the remainder of the molecule. Examples include the following compounds:

€ -NN ..NN .. ^ .NNk. ..NN. , NN _v .

^J -O -O .Q -N .4 ^ -) N

N _N .NL .N _N .N, λJ -O -Q

■ ύ - £ r ° -Cr ⁰ -Cr ⁰ The term "aryl" (including those which are part of other groups) are meant aromatic ring systems with 6 or 10 carbon atoms. For example, phenyl, 1-naphthyl or 2-naphthyl be mentioned; preferred aryl radical is phenyl. Unless otherwise stated, the aromatics may be substituted by one or more radicals selected from the group consisting of methyl, ethyl, n-propyl, / so-propyl, te / f-butyl, hydroxy, methoxy, trifluoromethoxy, fluorine, chlorine, bromine and iodine, where the radicals may be the same or different.

By the term "heteroaryl" is meant five- or six-membered heterocyclic aromatics having one, two, three or four heteroatoms selected from the group consisting of:

Group oxygen, sulfur and nitrogen, and in addition contain so many conjugated double bonds that an aromatic system is formed.

In addition, the term "heteroaryl" includes N-d-3-alkylated pyridones or pyrimidones.

These heteroaryls may additionally be benzo-fused with a phenyl ring to form nine- or ten-membered bicyclic heteroaryls.

Examples of five- or six-membered heterocyclic aromatics include:

C / _1-3 alkyl

Unless otherwise stated, the above-mentioned heteroaryls may be substituted by one or more radicals selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, tert-butyl, hydroxy, methoxy, trifluoromethoxy, fluoro, Chlorine, bromine and iodine, where the radicals may be the same or different. Furthermore, a nitrogen atom present in the heteroaryl radical may be oxidized to form an N-oxide.

If they contain suitable basic functions, for example amino groups, compounds of the general formula I and Ia can be converted, in particular for pharmaceutical applications, into their physiologically acceptable salts with inorganic or organic acids. Suitable inorganic acids are, for example, hydrobromic acid, phosphoric acid, nitric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid, organic acids being, for example, malic acid, succinic acid, acetic acid, fumaric acid, maleic acid, mandelic acid, lactic acid, tartaric acid or citric acid into consideration.

Furthermore, the compounds of the general formula I and Ia, if they contain suitable carboxylic acid functions, if desired, can be converted into their addition salts with inorganic or organic bases. Examples of suitable inorganic bases are alkali metal or alkaline earth metal hydroxides, for example sodium hydroxide or potassium hydroxide, or carbonates, ammonia, zinc hydroxides or ammonium hydroxides; suitable organic amines are, for example, diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine or dicyclohexylamine.

The compounds of the invention may exist as racemates if they possess only one chiral element, but they may also be present as pure enantiomers, i. in (R) or (S) form.

However, the application also includes the individual diastereomeric antipode pairs or mixtures thereof, which are present when more than one chiral element is present in the compounds of general formula I, as well as the individual optically active enantiomers which make up the racemates mentioned. PRODUCTION METHOD

According to the invention, the compounds of the general formula I are obtained by processes known per se from the literature and processes known to the person skilled in the art, for example by the following processes:

(A) Amide coupling:

(H) (Hl)

(B) Amide coupling:

(IV) (V)

The intermediate compounds III can be prepared by methods known from the literature, for example by the following processes:

(a) nucleophilic aromatic substitution: a) nucl. Substitution b) Deprotection ⁽ " ^I)

(VI) (UN)

PG represents a protecting group such as the te / f-butoxycarbonyl group or the benzyloxycarbonyl group, which can be cleaved again after the coupling step, for example by treatment with trifluoroacetic acid or HCl or by catalytic hydrogenation with palladium / carbon. Relevant reaction conditions are known from the literature or are described in the exemplary embodiments.

(b) palladium catalyzed aromatic substitution:

( ^VI) (VII)

PG is a protecting group such as the te / f-butoxycarbonyl group or the benzyloxycarbonyl group, which can be cleaved again after the coupling step, for example by treatment with trifluoroacetic acid or HCl or by catalytic hydrogenation with palladium / carbon. Relevant reaction conditions are known from the literature (Review: B. Schlummer, U. Scholz in Specialty Chemicals Magazine (2005), 25 (4), 22-24), for example, as a ligand for the palladium catalyst triphenylphosphine, (2-biphenyl) di-te / f Butylphosphine or (2-biphenyl) di-cyclohexyl-phosphine can be used.

Method Description for Binding to the Human BK1 Receptor (hBK1 Receptor)

CHO cells expressing the hBK1 receptor are cultured in "Dulbecco's modified medium." From confluent cultures, the medium is removed, the cells are washed with PBS buffer, scraped and isolated by centrifugation, then the cells are homogenized in suspension , the homogenate is centrifuged and resuspended. After determining the protein content of the membrane preparation thus obtained at -80 ⁰ C is frozen.

After thawing, 200 μl of the homogenate (50 to 100 μg protein / assay) is incubated for 60 minutes at room temperature with 0.5 to 1.0 nM kallidine (DesArg10, Leu9), [3,4-prolyl-3,43H (N)] and increasing concentrations the test substance in a total volume of 250 ul incubated. Incubation is terminated by rapid filtration through GF / B glass fiber filters pre-treated with polyethyleneimines (0.3%). The radioactivity bound to the protein is measured with a TopCount NXT. As non-specific binding, the bound radioactivity is defined in the presence of 1.0 μM kallidin (DesArgi 0, Leu9), [3,4-prolyl-3,43H (N)]. The analysis of the concentration Binding curve is done using a computer-aided nonlinear curve fitting. From the data thus obtained, the corresponding K, value is determined for the test substance.

Method Description for Binding to the cvnomolgus BK1 Receptor (cvnoBKI Receptor)

CHO flp in cells expressing the cynoBKI receptor are cultured in "HAM ^' S F-12 medium." Confluent cultures are used to remove the medium, wash the cells with PBS buffer, shave or peel off and pass through

Centrifuging isolated. Subsequently, the cells are homogenized in suspension, the homogenate is centrifuged and resuspended. After determination of the protein content of the membrane preparation thus obtained was frozen at -80 ⁰ C. After thawing, 200 μl of the homogenate (50 to 250 μg protein / assay) are incubated for 60-180 minutes at room temperature with 0.5 to 5.0 nM kallidin (DesArg10, l_eu9), [3,4-prolyl-3,43H (N)]. and increasing concentrations of the test substance in a total volume of 250 ul incubated. Incubation is terminated by rapid filtration through GF / B glass fiber filters pre-treated with polyethyleneimines (0.3%). The radioactivity bound to the protein is measured with a TopCount NXT. Non-specific binding is defined as the bound radioactivity in the presence of 1.0 μM (DesArgi O) kallidine. The analysis of the concentration-binding curve is carried out by means of a computer-aided non-linear curve fitting. From the data thus obtained, the corresponding K, value is determined for the test substance.

In order to show that the compounds of general formula I with different structural elements show good to very good bradykinin B1 receptor antagonistic activities, the following table gives the K values obtained according to the above experimental protocols.

INDICATIONS

Because of their pharmacological properties, the novel compounds and their physiologically acceptable salts are useful in the treatment of diseases and disease symptoms caused, at least in part, by the stimulation of bradykinin B1 receptors, or in which antagonizing the bradykinin-1 receptor can provide symptom relief ,

Due to their pharmacological properties, the substances are suitable for the treatment of (a) acute pain such as toothache, peri- and postoperative pain, traumatic pain, myalgia, burn pain, sunburn pain, trigeminal neuralgia, colic pain, and spasms of the stomach. Intestinal tract or uterus; (b) gastrointestinal pain, such as chronic pelvic pain, gynecological pain, pain before and during menstruation, pain in pancreatitis, peptic ulcer, interstitial cystitis, renal colic, cholecystitis, prostatitis, angina pectoris, pain in colonic irritable nonulcerous dyspepsia and in gastritis, prostatitis, non-cardiac chest pain and pain in myocardial ischemia and myocardial infarction; (c) neuropathic pain, such as painful polyneuropathies, pain in diabetic neuropathy, AIDS-associated neuropathic pain, non-herpes associated neuralgia, post-zoster neuralgia, nerve injury, traumatic brain injury, pain due to nerve damage as a result of toxins or chemotherapy, phantom pain, multiple sclerosis pain, nerve root tear and painful traumatic conditions

Single nerve damage, as well as central pain such as after stroke, spinal cord injury or tumors;

(d) inflammatory / pain receptor mediated pain associated with diseases such as osteoarthritis, rheumatoid arthritis, rheumatic fever, Tendo synovitis, bursitis, tendonitis, gout and gouty arthritis, traumatic arthritides, vulvodynia, muscle and fascia disorders and disorders , juvenile arthritis, spondylitis, psoriatic arthritis, myositides, dental disease, influenza and other viral infections such as colds, systemic lupus erythematosus or pain in burns; (e) tumor pain associated with cancers such as lymphocytic or myeloid leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, lymphogranulomatosis, lymphosarcoma, solid malignant tumors, and extensive metastases; (f) headache disorders of various causes, such as cluster headache, migraine (with or without aura), and tension-type headache; (g) pain conditions of mixed cause, such as chronic low back pain, including lumbago, or fibromyalgia.

Furthermore, the compounds are suitable for treatment

(h) inflammatory or inflammatory symptoms of sunburn and burns, gingivitis, edema after trauma from burns, cerebral edema and angioedema, bowel disease including Crohn's disease and ulcerative colitis, irritable bowel syndrome, pancreatitis, nephritis, cystitis (interstitial cystitis), uveitis; inflammatory diseases of the skin (such as psoriasis and eczema), vascular connective tissue disorders, strains and fractures, as well as musculoskeletal diseases with inflammatory phenomena such as acute rheumatic fever, polymyalgia rheumatica, reactive arthritis, rheumatoid arthritis, spondylarthritis, but also osseoarthritis, as well as inflammatory connective tissue diseases of others Genesis, and collagenoses of any genesis such as systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, Sjögren syndrome, Still's disease or Felty syndrome;

(i) of inflammatory changes associated with respiratory diseases such as bronchial asthma, including allergic asthma (atopic and non-atopic) and bronchospasm on exertion, occupational asthma, viral or bacterial exacerbation of existing asthma and other non-allergic conditional asthmatic diseases;

(j) chronic obstructive pulmonary disease (COPD) including pulmonary emphysema, adult respiratory distress syndrome (ARDS), bronchitis, pulmonary inflammation, allergic rhinitis (seasonal and perennial), vasomotor rhinitis and pneumoconiosis diseases such as aluminosis, anthracosis, asbestosis, Chalcosis, siderosis, silicosis, tobaccoosis and byssinosis and exogenous allergic alveolitides; (k) diabetes mellitus and its consequences (such as diabetic vasculopathy, diabetic neuropathy, diabetic retinopathy) and diabetic Symptoms of insulitis (eg hyperglycemia, diuresis, proteinuria and increased renal nitrite and kallikrein excretion);

(I) of sepsis and septic shock after bacterial infections or after

Trauma; (m) of itching (pruritus) causing syndromes and allergic

Skin reactions;

(n) from central nervous system injuries;

(o) wounds and tissue damage;

(p) benign prostatic hyperplasia and hyperactive bladder; (q) of vascular diseases such as panarteritis nodosa, polyarthritis nodosa,

Periarteritis nodosa, temporal arteritis, Wegner's granulomatosis, giant cell atritis,

Atherosclerosis, erythema nodosum;

(r) disorders of motility or spasm of respiratory, genitourinary, gastrointestinal inclusive biliary or vascular structures and organs; (s) post-operative fever;

(t) for the treatment and prevention of cardiovascular diseases such as hypertension and related disorders;

(u) for the treatment and prevention of cancer and related diseases;

(v) for the treatment and prevention of psychiatric disorders, such as depression;

(w) for the treatment and prevention of urinary incontinence and related diseases

diseases;

(x) for the treatment and prevention of diseased obesity and relatives

diseases; (y) for the treatment and prevention of arteriosclerosis and related diseases

Diseases.

The substances are suitable for causal treatment in terms of slowing down or stopping the progression of chronic progressive diseases, in particular osteoarthritis, rheumatoid arthritis and spondylarthritis.

By the term "treatment" or "therapy" is meant a therapeutic treatment of patients with overt, acute or chronic indications, wherein on the one hand the symptomatic (palliative) treatment for the relief of the disease symptoms and on the other hand the causal or curative treatment of the indication with the aim to end the pathological condition, to reduce the severity of the pathological condition or to delay the progression of the pathological condition, depending on the species or severity of the indication included.

Another object of the present invention is the use of a compound of general formula I or Ia for the manufacture of a medicament for the acute and prophylactic treatment of acute pain, intestinal pain, neuropathic pain, inflammatory / pain receptor-mediated pain, cancer pain and headache disorders. The use is characterized in that it involves the administration of an effective amount of a compound of general formula I or a physiologically acceptable salt thereof to a patient in need of such treatment.

The term "patient" is preferably understood to mean a human.

In addition to their suitability as human therapeutics, these substances are also useful in the veterinary treatment of pets, exotic animals and livestock.

COMBINATIONS

For the treatment of pain, it may be advantageous to combine the compounds of the invention with invigorating substances such as caffeine or other analgesic agents. If suitable active ingredients are available for the treatment of the cause of the pain, these can be combined with the compounds according to the invention.

For a combination therapy, for example, the following compounds come into question:

Non-steroidal anti-inflammatory drugs (NSAIDs), such as propionic acid derivatives, which may be selected from the group consisting of alminoprofen, benoxaprofen, bucloxinic acid, carprofen, fenoprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen , Tiaprofenic acid and tioxaprofen; Acetic acid derivatives which may be selected from the group consisting of indomethacin, acemetacin, alcofenac, isoxepac, sulindac, tiopinac, tolmetin, zidometacin and zomepirac; Fenamic acid derivatives which may be selected from the group consisting of meclofenamic acid, mefenamic acid and tolfenamic acid; Biphenyl carboxylic acid derivatives; Oxicams, which may be selected from the group consisting of isoxicam, meloxicam, piroxicam, sudoxicam and tenoxicam; Salicylic acid derivatives which may be selected from the group consisting of acetylsalicylic acid and sulfasalazine; Pyrazolones, which may be selected from the group consisting of apazone, benzpiperylon, feprazone, mofebutazone, oxyphenbutazone and phenylbutazone); Coxibs, which may be selected from the group consisting of celecoxib, valecoxib, rofecoxib and etoricoxib.

Opiate receptor agonists, which may be selected, for example, from the group consisting of such as morphine, darvon, tramadol and buprenorphine.

Cannabinoid agonists, which may for example be selected from the group consisting of GW-1000, GW-843166 and GW-842166X.

Sodium channel blockers, which may be selected, for example, from the group consisting of carbamazepine, mexiletine, lamotrigine, pregabalin, tectin, NW-1029 and CGX-1002.

N-type calcium channel blockers, which may be selected, for example, from the group consisting of ziconitide, NMED-160 and SP1-860.

Serotonergic and noradrenergic modulators, which may be selected, for example, from the group consisting of paroxetine, duloxetine, amitriptyline, citalopram.

Corticosteroids, which may be selected, for example, from the group consisting of betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone.

Histamine H1 receptor antagonists, which may be selected, for example, from the group consisting of bromophtniramine, chlorpheniramine, dexchlorpheniramine, Triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine, pyrilamine, astemizole, terfenadine, loratadine, cetirizine, desloratadine, fexofenadine and levocetirizine.

Leukotriene antagonists and 5-lipoxygenase inhibitors, which may for example be selected from the group consisting of zafirlukast, montelukast, pranlukast and zileuton.

Local anesthetics, which may be selected, for example, from the group consisting of ambroxol and lidocaine.

VR1 agonists and antagonists, which may be selected, for example, from the group consisting of NGX-4010, WL-1002, ALGRX-4975, WL-10001 and AMG-517.

Nicotine receptor agonists, which may be selected, for example, from the group consisting of ABT-202, A-366833, ABT-594, BTG-102, A-85380 and CGX1204.

P2X3 receptor antagonists, which may be selected, for example, from the group consisting of A-317491, ISIS-13920 and AZD-9056.

NGF agonists and antagonists, which may be selected, for example, from the group consisting of RI-724, RI-1024, AMG-819, AMG-403 and PPH 207.

NK1 and NK2 antagonists, which may for example be selected from the group consisting of DA-5018, R-116301, CP-728663 and ZD-2249.

NMDA antagonists, which may be selected, for example, from the group consisting of NER-MD-1 1, CNS-5161, EAA-090, AZ-756 and CNP-3381.

Potassium channel modulators, which may be selected, for example, from the group consisting of CL-888, ICA-69673 and retigabine.

GABA modulators, which may be selected, for example, from the group consisting of baclofen and lacosamide. Anti-migraine therapeutics, which may be selected, for example, from the group consisting of sumatriptan, zolmitriptan, naratriptan and eletriptan.

The dose required to produce an analgesic effect is advantageously 0.01 to 3 mg / kg body weight, preferably 0.1 to 1 mg / kg when given intravenously, and 0.1 to 8 mg / kg body weight, preferably 0.5 to 3 mg / kg, respectively, when given orally 1 to 3 times a day. The compounds prepared according to the invention can be administered intravenously, subcutaneously, intramuscularly, intrarectally, intranasally, by inhalation, transdermally or orally, with aerosol formulations in particular being suitable for inhalation. Optionally they may be combined with one or more inert conventional carriers and / or diluents, e.g. with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or their suitable mixtures, in customary pharmaceutical preparations such as tablets, dragees, capsules, powders, suspensions, solutions, metered aerosols or suppositories are incorporated.

EXPERIMENTAL PART

As a rule, mass spectra and / or ¹ H-NMR spectra are available for the compounds prepared. The ratios indicated for the flow agents relate to volume units of the respective solvents. The volume units given for ammonia refer to a concentrated solution of ammonia in water. Unless otherwise stated, the acid, base and salt solutions used in the workup of the reaction solutions are aqueous systems of the indicated concentrations.

For chromatographic purifications, silica gel from Millipore (MATREX ™, 35 to 70 μm) or Alox (E. Merck, Darmstadt, aluminum oxide 90 standardized, 63 to 200 μm, article no: 1.01097.9050) is used.

In the test descriptions, the following abbreviations are used: Alox alumina

BOC te / f-butoxycarbonyl DC thin-layer chromatogram

DCM dichloromethane

DMF Λ /, Λ / -dimethylformamide

DMSO dimethyl sulfoxide

NMP 1 -methylpyrrolidine

EE ethyl acetate

HCl hydrochloric acid

KG silica gel

MeOH methanol

PE petroleum ether

RT room temperature

TEA triethylamine

TBTU 2- (1 / - / - Benzotriazol-1-yl) -1,3,3-tetramethyluronium tetrafluoroborate tert-tertiary

TFA trifluoroacetic acid

THF tetrahydrofuran

BOC anhydride di-tert-butyl dicarbonate

The following analytical HPLC methods are used:

Method 1: Column: Interchim Strategy C18, 5 μM, 4.6 x 50 mm

Detection: 220 - 320 nm

Plasticizer A: water / 0.1% TFA

Plasticizer B: acetonitrile

Gradient:

Method 2: Column: Varian XRS C18, 5 μM, 4.6 x 50 mm Detection: 254 & 220-320 nm

Plasticizer A: water / 0.1% formic acid

Plasticizer B: acetonitrile gradient:

Method 3: Column: Sunfire C18, 3.5 uM, 4.6 x 50 mm (40.0 ⁰ C)

Detection: 210 500 nm

Plasticizer A: water / 0.1% TFA

Plasticizer B: acetonitrile / 0.1% TFA

Gradient:

Method 4: Column: Xbridge C18, 3.5 uM, 4.6 x 50 mm (40.0 ⁰ C)

Detection: 210 500 nm

Plasticizer A: water / 0.1% TFA

Plasticizer B: acetonitrile gradient:

The following preparative methods are used for reversed-phase chromatography:

Method 1: Column: Varian C18 Microsorb

Detection: UV controlled

Flow agent A: water / 0.2% trifluoroacetic acid

Plasticizer B: acetonitrile

Gradient:

Method 2: Column: Waters XBridge, C18; 5 μM, 50 x 150 mm

Detection: UV controlled

Plasticizer A: water / 0.3% ammonia

Plasticizer B: acetonitrile

Gradient:

Method 3: Column: Waters Sunfire, C18; 10 μ, 30 x 100 mm Detection: UV / MS triggered

Plasticizer A: water / 0.1% TFA

Plasticizer B: acetonitrile gradient:

Example 1: Pyrimidine-5-carboxylic acid N- {1- [1 - (3-chloro-2-methoxycarbonyl-phenyl) -piperidin-4-ylmethylcarbamoyl] -cyclopropyl} -amide

1 a) 2-chloro-6-fluoro-benzoic acid methyl ester

5.0 g (28.6 mmol) of 2-chloro-6-fluorobenzoic acid are suspended in MeOH and heated to 60 ⁰ C. Then slowly 3.8 ml (51.7 mmol) of thionyl chloride are added dropwise and it is stirred overnight at 60 ⁰ C. Concentrate the reaction mixture and add semisaturated potassium carbonate solution. The solution is treated with 1 molar NaOH and extracted with DCM / MeOH. The organic phase is separated, over

Dried sodium sulfate and concentrated in vacuo.

Yield: 55% of theory

C ₈ H ₆ CIFO ₂ (188.583)

HPLC: RT = 1.903 min (method 1) 1 b) methyl 2- [4- (tert-butoxycarbonylamino-methyl) -piperidin-1-yl1-6-chloro-benzoate

A mixture of 8.0 g (42.4 mmol) of 2-chloro-6-fluoro-benzoic acid methyl ester and 10.0 g (46.7 mmol) of piperidin-4-ylmethyl-carbamic acid tert-butyl ester in 48 ml of DMF is mixed with 14.7 g (106.1 mmol). Potassium carbonate added and stirred at 130 ⁰ C for 4 h. The reaction mixture is taken up in EA and shaken out with semisaturated potassium carbonate solution. The EE phase is dried over sodium sulfate and concentrated. The residue is purified by preparative HPLC (Method 1). Yield: 8% of theory CI ₉ H ₂₇ CIN ₂ O ₄ (382.88)

Mass spectrum: [M + H] ⁺ = 383/385 (Cl) HPLC: RT = 2.206 min (Method 1)

1 c) methyl 2- (4-aminomethyl-piperidin-1-yl) -6-chloro-benzoate 4.7 g (12.4 mmol) of 2- [4 - [(te / f-butoxycarbonylamino-methyl) -piperidin-1-yl] Methyl 6-chlorobenzoate are suspended in 80 ml of 4 N HCl and stirred at RT overnight. Then the reaction mixture is concentrated in vacuo and the residue is purified by preparative HPLC (Method 1). The residue is mixed with 6 molar HCl and concentrated again. For further purification, it is separated by means of basic HPLC (Method 2).

Yield: 8% of theory.

Mass spectrum: [M + H] ⁺ = 283/285 (Cl) HPLC: RT = 1.343 min (method 1)

1 d) pyrimidine-5-carboxylic acid

10.0 g (65.7 mmol) of pyrimidine-5-carboxylic acid ethyl ester are mixed with 12 ml of 6 molar NaOH and stirred at RT. It is then cooled and made slightly acidic with 6 molar HCl (about 8 ml). The precipitate formed is filtered off with suction, washed with isopropanol and dried.

Yield: 83% of theory

C ₅ H ₄ N ₂ O ₂ (124.1)

Mass spectrum: [MH] - = 123 1 e) Ethyl 1- (pyrimidine-5-carbonyl) -amino-cyclopropanecarboxylate To a solution of 6.8 g (55 mmol) of pyrimidine-5-carboxylic acid in 200 ml of THF are added 18.8 ml (135 mmol) of triethylamine and 19.3 g (60 mmol) of TBTU added and stirred for 30 min at RT. Then 9.1 g (55 mmol) of 1-amino-cyclopropanecarboxylic acid ethyl ester are added and everything stirred together at RT overnight. Then the mixture is evaporated to dryness. The residue is first mixed with water and then made alkaline with dilute potassium carbonate solution. The aqueous phase is extracted with EA. The combined organic phases are washed with saturated NaCl solution, dried and concentrated. The residue is purified by chromatography over a KG column (gradient: DCM / MeOH 100: 0-96-4). Yield: 88% of theory

CnH ₁₃ N ₃ O ₃ (235.23)

Mass spectrum: [M + H] + = 236

1f) 1- (pyrimidine-5-carbonyl) amino-cyclopropanecarboxylic acid

1 1.0 g (47 mmol) of 1- (pyrimidine-5-carbonyl) amino-cyclopropanecarboxylic acid ethyl ester are suspended in 200 ml MeOH and treated with 65 ml (130 mmol) 2 M NaOH. The mixture is stirred at 50 ^° C. for 1 h. The mixture is then neutralized with glacial acetic acid and evaporated. The residue is dissolved in water and separated by preparative HPLC (Method 1).

Yield: 51% of theory

C ₉ H ₉ N ₃ O ₃ (207.19)

1 g) pyrimidine-δ-carboxylic acid-N-li-fi-O-chloro-1-methoxycarbonyl-phenvD-piperidin-1-ylmethylcarbamoyl-cyclopropyl-amide

95 mg (0.5 mmol) of 1- (pyrimidine-5-carbonyl) amino-cyclopropanecarboxylic acid are initially charged in 5 ml of DMF and admixed with 0.14 ml (1.0 mmol) of triethylamine and 157.6 mg (0.5 mmol) of TBTU. The mixture is stirred for 10 min and then treated with 95.1 mg (4.6 mmol) 2- (4-aminomethyl-piperidin-1-yl) -6-chloro-benzoic acid methyl ester in 30 ml of THF. All together is stirred for 2 h at RT. The batch is then concentrated and the residue is purified by preparative HPLC (method 1). Yield: 76% of theory

C ₂₃ H ₂₆ CIN ₅ O ₄ (471.94)

Mass spectrum: [M + H] + = 472/474 (Cl) HPLC: RT = 1.721 min (method 1)

Example 2: Pyrimidine-5-carboxylic acid N- {1- [1 - (3-fluoro-2-methoxycarbonyl-phenyl) -piperidine] -ylmethylcarbamoyl-O-cyclopropyl-amide

2a) 2- [4- (te / f-butoxycarbonylamino-methyl) -piperidin-1-yl1-6-fluoro-benzoic acid methyl ester

3.0 g (17.4 mmol) of methyl 2,6-difluorobenzoate are suspended in 20 ml of DMF with 4.1 g (19.2 mmol) of piperidin-4-ylmethyl-carbamic acid tert-butyl ester and 4.8 g (34.9 mmol) of potassium carbonate and dried overnight (18 h) at 130 ⁰ C stirred. The mixture is then concentrated in vacuo and the residue is semi-saturated

Added potassium carbonate solution. The aqueous phase is extracted three times with DCM and the combined organic phases are dried over sodium sulfate and concentrated. The residue is purified by chromatography over a KG column (gradient: PE / EA 4: 1).

Yield: 46% of theory

Mass spectrum: [M + H] + = 367 HPLC: RT = 2.197 min (method 1)

2b) 2- (4-Aminomethylpiperidin-1-yl) -6-fluoro-benzoic acid methyl ester hydrochloride 3.0 g (8.1 mmol) 2- [4 - [(te / f-butoxycarbonylamino-methyl) -piperidin-1-yl] Methyl 6-fluorobenzoate are suspended in 20 ml of 4N HCl in dioxane and stirred at RT overnight. Then the reaction mixture is concentrated on a rotary evaporator. Ci ₄ H ₁₉ FN ₂ O ₂ ΗCI (302.77) mass spectrum: [M + H] ⁺ = 267 HPLC: RT = 1.269 min (method 1) 2c) pyrimidine-δ-carboxylic acid N-li-fi-O-fluoro-methoxycarbonyl-phenvD-piperidine

4-ylmethylcarbamoyl1-cvclopropyl) -amide

The title compound is prepared starting from 2- (4-aminomethyl-piperidin-1-yl) -6-fluoro-benzoic acid methyl ester (2b) and (1f) analogously to Example (1 g). Yield: 21% of theory

C ₂₃ H ₂₆ FN ₅ O ₄ (455.48)

Mass spectrum: [M + H] + = 456 HPLC: RT = 1.621 min (method 1)

Example 3: 2-Methoxy-pyrimidine-5-carboxylic acid N- {1- [1- (3-fluoro-2-methoxycarbonyl-phenoxy-piperidine] -ylmethyl-carbamoyl-1-cyclopropyl-1-amide

3a) Methyl 2- [4- (te / f-butoxycarbonylamino) -cyclopropyl-carbonylaminomethyl) -piperidine-1-yl-6-fluorobenzoate

Analogously to Example (1g), the title compound is prepared starting from 1- (N-te / f-Boc-amino) -cyclopropanecarboxylic acid, and (2b).

Yield: 78.7% of theory

Mass spectrum: [M + H] + = 450

HPLC: RT = 1.978 min (method 1)

3b) Methyl 2- [4- (1-amino-cyclopropyl-carbonylaminometh-1-piperidin-1-yl) -6-fluoro-benzoate hydrochloride Analogously to Example (2b), the title compound is prepared from (3a). Yield: quantitative

Ci ₈ H ₂₄ FN ₃ O ₃ ΗCI (385.86) Mass spectrum: [M + H] + = 350 HPLC: RT = 1.302 min (method 1) 3c) 2-Methoxy-pyrimidine-5-carboxylic acid N- {1- [1 - (3-fluoro-2-methoxycarbonyl-phenyl) -piperidin-4-ylmethylcarbamoyl-1-cyclopropyl) -amide

Analogously to Example (1 g), the title compound is prepared starting from 2-methoxy-pyrimidine-5-carboxylic acid and (3b). C ₂₄ H ₂₈ FN ₅ O ₅ (485.51)

Mass spectrum: [M + H] + = 486 HPLC: RT = 1.57 min (Method 3)

Example 4: Pyrimidine-5-carboxylic acid N- {1- [1- (3-fluoro-2-trifluoromethyl-phenyl) -piperidin-4-ylmethylcarbamoyl] -cyclopropyl} -amide

4a) [i-O-fluoro-trifluoromethvl-phenvD-piperidine] -ylmethyl-carbamic acid te / f-butyl ester

Analogously to Example (2a), piperidin-4-ylmethyl-carbamic acid-t / f-butyl ester and 2,6-

Difluorobenzotrifluoride produced the title compound.

Yield: 30% of theory

Mass spectrum: [M + H] ⁺ = 377

HPLC: 2.395 min (method 1)

4b) [1- (3-Fluoro-2-trifluoromethyl-phenyl) -piperidin-4-yl-1-methylamine hydrochloride] The title compound from Example (4a) is prepared analogously to Example (2b). Ci ₃ H ₁₆ F ₄ N ₂ ΗCl (312.73)

Mass spectrum: [M + H] ⁺ = 277

4c) Pyrimidine-5-carboxylic acid N- {1- [1- (3-fluoro-2-trifluoromethyl-phenyl) -piperidin-4-yl-methylcarbamoyl-cioclopropyl-amide Analogously to Example (1 g), the title compound is prepared starting from (1f) and (4b).

Yield: 58% of theory

Mass spectrum: [M + H] + = 466

[MH] ^" = 464

HPLC: 1.836 min (method 1)

Example 5: Pyrimidine-5-carboxylic acid N - {1- [1- (3-chloro-2-aminocarbonyl-phenyl) -piperidine] -ylmethyl-carbamoyl-cyclopropyl-amide

5a) [i-Q-chloro-c-phen-phenvD-piperidine] -ylmethyl-carbamic acid-tert-butyl ester

A mixture of 0.5 g (3.2 mmol) 2-chloro-6-fluoro-benzonitrile and 0.76 g (3.54 mmol)

Piperidin-4-ylmethyl-carbamic acid fe / f-butyl ester in 3.64 ml of DMF were treated with 0.89 g (6.43 mmol) of potassium carbonate and stirred at 130 ⁰ C for 3 h. The reaction mixture is taken up in EA and shaken out with semisaturated potassium carbonate solution.

The EE phase is dried over sodium sulfate and concentrated.

Yield: 78% of theory

Mass spectrum: [M + H] + = 350/52 (Cl)

HPLC: 2.177 min (Method 1)

5b) 2- (4-Aminomethyl-piperidin-1-yl) -6-chloro-benzamide sulphate 1.08 g (3.08 mmol) of tert -butyl tert-butyl [S-chloro-cyano-phenyl-1-piperidine] -ylmethyl-1-carbamate are suspended in 1.24 ml (22 mmol) of sulfuric acid and stirred at RT for 24 h, then a further 1 ml of sulfuric acid is added and the mixture is stirred at RT for a further 48 h, ice is added to the reaction mixture and purified by preparative HPLC (method 1) : 46% of theory Ci ₃ H ₁₈ CIN ₃ CTI-I ₂ O ₄ S (365.83) Mass spectrum: [M + H] + = 268/70 (Cl) HPLC: 1.062 min (method 1)

5c) Pyrimidine-δ-carboxylic acid-N-li-fi-O-chloro-aminocarbonyl-phenvD-piperidine ^ -yl-methylcarbamoyl-cyclopropyl-amide

Analogously to Example (1 g), the title compound is prepared starting from (1f) and (5b).

Yield: 89% of theory

C ₂₂ H ₂₅ Cl N ₆ O ₃ (456.93) Mass spectrum: [M + H] + = 457/59 (Cl)

HPLC: 1.401 min (method 1)

Example 6: Isoxazole-5-carboxylic acid N - {1- [1- (3-chloro-2-methoxycarbonyl-phenyl) -piperidine] -ylmethylcarbamoyl-cyclopropyl-amide

6a) 2-chloro-6-fluoro-benzoic acid methyl ester

To 12.4 g (64.3 mmol) of 2-chloro-6-fluoro-benzoyl chloride, 24.8 ml of 618.6 mmol) of MeOH are slowly added dropwise. The solution is stirred for 24 h at RT and then concentrated. Yield: 99% of theory

C ₈ H ₆ CIFO ₂ (188.58)

GC-MS: M + = 188/190 (CI)

6b) methyl 2- [4- (tert-butoxycarbonylamino-methyl) -piperidin-1-yl1-6-chloro-benzoate

The title compound is prepared from piperidin-4-ylmethyl-carbamic acid-tert-butyl ester and (6a) analogously to Example (2a).

Yield: 8% of theory

Mass spectrum: [M + H] ⁺ = 383/85 (Cl)

HPLC: 2.206 min (method 1) 6c) Methyl 2- (4-aminomethyl-piperidin-1-yl) -6-chloro-benzoate The title compound from Example (6b) is prepared analogously to Example (2b). CI ₄ H ₁₉ CI N ₂ O ₂ ^* HCl (319.23) Mass spectrum: [M + H] ⁺ = 283/285 (Cl) HPLC: 1344 min (method 1)

6d) Methyl 2- [4- (1-amino-cyclopropyl) -carbonylaminomethyl) -piperidin-1-yl1-6-chloro-benzoate 0.66 g (3.3 mmol) of 1- (N-te / f-Boc-amino) Cyclopropanecarboxylic acid are dissolved in 30 ml DMF and admixed with 1.06 g (3.3 mmol) TBTU, and 1.2 ml (8.6 mmol) TEA. The reaction mixture is stirred for 5 min at RT and then added to 1.05 g (3.3 mmol) (6c) and stirred for a further 24 h at RT. The reaction mixture is then filtered through Alox B, washed with DMF: MeOH = 9: 1 and concentrated. The residue is combined with 20 ml DCM: TFA = 1: 1 and stirred for 1 h at RT. After rotation, make alkaline with 32% ammonia solution and mixed with DCM. The two-phase mixture is purified over a KG column (gradient: DCM + 0-10% MeOH: NH 4 OH = 9: 1). Yield: 57% of theory

Mass spectrum: [M + H] ⁺ = 366/68 (Cl) HPLC: 1.81 min (method 3)

6e) isoxazole-δ-carboxylic acid-N-li-fi-O-chloro-1-methoxycarbonyl-phenvD-piperidine-1-methylcarbamoyl-cyclopropyl-D-amide

36.6 mg (100 μmol) (6d) are initially charged in 3 ml of acetonitrile and successively with 30 μl

TEA and 14.5 mg (1 10 .mu.mol) isoxazole-5-carbonyl chloride and shaken at RT for 48 h. The reaction mixture is purified by preparative HPLC (Method 3).

Yield: 43% of theory C ₂₂ H ₂₅ CIN ₄ O ₅ (460.92)

Mass spectrum: [M + H] ⁺ = 461/63 (Cl)

HPLC: 2.01 min (Method 3) Example 77: Pyrimidine-5-carboxylic acid N - {1- [1- (2-methoxycarbonyl-5- (thien-2-yl) -phenyl) -piperidin-4-ylmethylcarbamoyl] -cyclopropyl} -amide

77a) Methyl 4-bromo-2-fluorobenzoate

500 mg (2.1 mmol) 4-bromo-2-fluorobenzoyl chloride are added dropwise in 0.81 ml MeOH and then stirred for 1 h at RT. The reaction mixture is then concentrated.

Yield: 98.4% of theory

C ₈ H ₆ BrFO ₂ (233.03)

Mass spectrum: [M + H] + = 233/235 (Br)

HPLC: RT = 2.075 min (method 2)

77b) methyl 2-fluoro-4- (thien-2-yl) benzoate

480 mg (2.07 mmol) of (77a), 320 mg (2.49 mmol) of thien-2-ylboronic acid and 119.76 mg (0.1 mmol) of palladium tetrakistriphenylphosphine in 2.07 ml of 2M aqueous sodium carbonate solution and 8.29 ml of dioxane are added in the microwave for 45 minutes 90 ⁰ C stirred. The

The reaction mixture is filtered off with suction through a glass fiber filter and the filtrate is concentrated.

The residue is dissolved in EA and washed with water and saturated NaCl solution. The combined organic phases are dried over Na ₂ SO ₄ and concentrated. The residue is recrystallized from methanol.

Yield: 54% of theory

Mass spectrum: [M + H] + = 237

HPLC: RT = 2.206 min (method 2)

77c) Methyl 2- (4 - ((te / f-butoxycarbonylamino) methyl) piperidin-1-yl) -4- (thien-2-yl) benzoate The title compound is prepared from piperidin-4-ylmethyl-carbamic acid-t / f-butyl ester and example (77b) analogously to Example (2a). Yield: 74% of theory

C ₂₃ H ₃₀ N ₂ O ₄ S (430.56) Mass spectrum: [M + H] ⁺ = 431

HPLC: 2.042 min (method 2)

77d) Methyl 2- [4- (aminomethyl) piperidin-1-yl-4-thien-2-yl) benzoate hydrochloride The title compound from Example (77c) is prepared analogously to Example (2b). Ci ₈ H ₂₂ N ₂ O ₂ S ΗCl (366.91)

Mass spectrum: [M + H] ⁺ = 331

HPLC: 1 .298 min (method 2)

77e) Pyrimidine-5-carboxylic acid N - {1- [1- (2-methoxycarbonyl-5- (thien-2-yl) -phenyl) -piperidine-1-methyl-1-carbamoyl-cyclopropyl-D-amide

Analogously to Example (1 g), the title compound is prepared starting from (1f) and (77d).

Yield: 16% of theory

C ₂₇ H ₂₉ N ₅ O ₄ S (519.62)

Mass spectrum: [M + H] + = 520 HPLC: 1 .437 min (Method 2)

Example 78: Pyrimidine-5-carboxylic acid N- {1- [1- (5-fluoro-4-methoxycarbonyl-pyridin-3-yl) -piperidin-4-ylmethylcarbamoyl] -cyclopropyl} -amide hydrochloride

78a) Methyl 3,5-difluoroisonicotinate

300 mg (1.89 mmol) of 3,5-difluoroisonicotinic acid are dissolved in 5 ml MeOH u. heated to 80 ⁰ C. Then 0.3 ml of conc. H ₂ SO _{4 was} added and stirred at 80 ⁰ C for 6 h. Overnight the reaction is allowed to stand at RT. The reaction mixture is then concentrated. The residue is taken up in methylene chloride washed with 1 Mk ₂ Cθ3 solution and the organic phase dried over Na ₂ SO ₄ u. evaporated. Yield: 55% of theory

C ₇ H ₅ F ₂ NO ₂ (173.12) Mass spectrum: [M] + = 173

HPLC: RT = 1.608 min (method 1)

78b) 4- (aminomethyl) piperidine-1-carboxylic acid te / f-butyl ester

41 ml (0.4 mol) of benzaldehyde are added to a solution of 45 g (0.4 mol) of 4- (aminomethyl) -piperidine in toluene and boiled for 5 hours on a water separator. The reaction is cooled to RT and treated with 96 g (0.44 mol) of Boc anhydride. The reaction mixture is stirred overnight at RT and then concentrated. The residue is treated with potassium hydrogen sulfate solution, stirred for 4 h and washed three times with te / f-butyl methyl ether. Subsequently, the aqueous phase is made strongly alkaline with sodium hydroxide solution and extracted several times with DCM. The combined organic extracts are dried over MgSO ₄ and concentrated. Yield: 90% of theory

CnH ₂₂ N ₂ O ₂ (214.31)

Mass spectrum: [M + H] + = 215

78c) pyrimidine-δ-carboxylic acid N-li-fi-terfcutoxycarbonyl-piperidine ^ -ylmethyl-carbamoyl-cyclopropyl-D-amide

Analogously to Example (1 g), the title compound is prepared starting from (1f) and Example (78b). Yield: 84.8% of theory

C ₂₀ H ₂₉ N ₅ O ₄ (403.48)

Mass spectrum: [M + H] + = 404 HPLC: 1 .536 min (Method 1)

78d) pyrimidine-δ-carboxylic acid N-li-fi-ter-di-pentoxycarbonyl-piperidine ^ -ylmethane-carbamoyl-cyclopropyl-D-amide

The title compound from Example (78c) is prepared analogously to Example (2b) and reacted further without further purification. Ci ₅ H ₂₁ N ₅ O ₂ ^* HCI (339.82) Mass spectrum: [M + H] ⁺ = 304

78e) pyrimidine-δ-carboxylic acid N-li-fi-fδ-fluoro-methoxycarbonyl-pyridine-S-vD-piperidine

4-ylmethylcarbamoyl-1-cyclopropyl) amide hydrochloride

100 mg (0.29 mmol) of Example (78d), 56 mg (0.32 mmol) of Example (78a) and 0.12 ml (0.68 mmol) of TEA are stirred in 1 ml of DMSO at 1 10 ⁰ C for 4 h. The reaction mixture is purified by preparative HPLC (Method 1) and then treated with hydrochloric acid and freeze-dried.

Yield: 10% of theory

C ₂₂ H ₂₅ N ₆ O ₄ ^* H Cl (492.93)

Mass spectrum: [M + H] + = 457

HPLC: 1.476 min (method 1)

The remaining compounds are prepared analogously to the above-mentioned examples or by literature methods.

The compounds according to the invention are summarized in Table 1.

Table 1

The following examples describe pharmaceutical dosage forms containing as active ingredient any compound of the general formula I, but without limiting the scope of the present invention to this:

example

Dry ampoule containing 75 mg of active ingredient per 10 ml

Composition:

Active ingredient 75 .0 mg

Mannitol 500 mg water for injections ad 10 .0 ml

production:

Active substance and mannitol are dissolved in water. After bottling is freeze-dried.

The solution to the ready-to-use solution is water for injections.

Example Il

Tablet with 50 mg active ingredient

Composition:

(1) Active ingredient 50.0 mg (2) lactose 98.0 mg

(3) Cornstarch 50.0 mg

(4) polyvinylpyrrolidone 15.0 mg

(5) Magnesium stearate 2.0 mg

215. 0 mg

production:

(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). The dried granules are admixed with (5). From this mixture tablets are pressed, biplan with double-sided facet and one-sided part notch. Diameter of the tablets: 9 mm.

example

Tablet with 350 mg active ingredient

Composition:

(1) Active ingredient 350 .0 mg

(2) lactose 136 .0 mg

(3) corn starch 80 .0 mg

(4) polyvinylpyrrolidone 30 .0 mg

(5) Magnesium stearate 4 .0 mg

600 .0 mg

production:

(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). The dried granules are admixed with (5). From this mixture tablets are pressed, biplan with double-sided facet and one-sided part notch. Diameter of the tablets: 12 mm.

Example IV

Capsules with 50 mg active ingredient Composition:

(1) Active ingredient 50.0 mg

(2) corn starch dried 58.0 mg (3) lactose powdered 50.0 mg

(4) Magnesium stearate 2.0 mg

160.0 mg

Preparation: (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) under intensive mixing.

This powder mixture is filled on a capsule filling machine into size 3 hard gelatine capsules.

Example V

Capsules with 350 mg active ingredient

Composition: (1) Active ingredient 350.0 mg

(2) corn starch dried 46.0 mg

(3) lactose powdered 30.0 mg

(4) magnesium stearate 4.0 mg

430.0 mg

production:

(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) under intensive mixing.

This powder mixture is filled on a capsule filling machine in hard gelatin capsules Gr6Be 0.

Example VI

Suppositories containing 100 mg of active ingredient 1 suppository contains:

Active ingredient 100.0 mg

Polyethylene glycol (M.G. 1500) 600.0 mg

Polyethylene glycol (M.G. 6000) 460.0 mg

Polyethylene sorbitan monostearate 840.0 mg

2000.0 mg

Claims

claims

1. Compounds of the formula I,

in the

a direct bond, a -CH ₂ -, -CH ₄ -CH ₂ - or a CH ₂ -CH ₂ -CH ₂ - group;

R ^{1 is} (a) a phenyl group which may be optionally substituted with 1, 2 or 3 R ^{1 1} radicals;

(b) a 5- or 6-membered heteroaryl group which may optionally be substituted with one or two of R ^1-2 ;

1.1 independently

(a) halogen,

(b) d-3-alkyl which is optionally partially or fully fluorinated;

(c) -OH; -Od- _3- alkyl which is optionally partially or completely fluorinated;

(d) -NR ^{1 2 1} R ¹ - ²² ,

(e) -CN;

»1.2 independently

(a) halogen,

(b) d-3-alkyl which is optionally partially or fully fluorinated; (C) -OH, -Od- _3- alkyl,

(d) -NR ^{1 2 1} R ¹ - ²² ,

(e) -CN;

R ¹ - ² - ¹ , R ¹ - ² - ^{2 are} independently (a) H, (b) Ci-3-alkyl, or together form a C _3- 7-alkylene group;

_R 2a _R 2b independently

(a) H or

(b) Ci-8-alkyl;

R ³ (a) H or

(b) Ci-6-alkyl;

R ⁴ (a) a PhenvIαruoD, 4.1 may be substituted,

(b) a 5- or 6-membered heteroaryl group which may optionally be substituted with 1, 2 or 3 R ⁴² radicals;

, 4.1 independently

(a) halogen,

(b) d-3-alkyl which is optionally partially or fully fluorinated; (C) -COO-R ⁴ - ¹ - ¹ , (d) -CO-R ^{4 1 2} ,

(e) -CN,

(f) -OH, -O-Ci-3-alkyl, -O-CH ₂ CF ₃ ,

(g) -NR ^{4 1 3} R ⁴ - ^{1 4} , (h) phenyl, (i) heteroaryl or

(j) a heterocyclic ring, in particular selected from

R ⁴ - ¹ - ¹ (a) H,

(b) C _1-3 alkyl, (c) benzyl; »4.1.2 (a) -NR ^{4 1 2 1} R ⁴ - ¹ - ² - ² ,

(b) C _1-3 alkyl;

R ⁴ - ¹ - ³ , R ⁴ - ¹ - ⁴ independently of one another (a) H,

(b) C _1-3 alkyl,

(C) -C (O) -Ci _-3 -alkyl,

(d) -C (O) -C ₃ -C ₇ -cycloalkyl,

(e) benzoyl;

R ⁴ - ¹ - ² - ¹ , R ⁴ - ¹ - ² - ^{2 are} independent of each other

(a) H,

(b) C _1-3 alkyl,

(C) C _3-7 cycloalkyl, (d) benzyl; or

R ⁴ - ¹ - ² - ¹ and R ⁴ - ¹ - ² - ² together with the N-atom to which they are attached, can form a 4-, 5- or 6-membered heterocyclic ring, which is additionally a further heteroatom selected from N, O and S may contain;

R ⁴ - ^{2 are} independent of each other

(a) halogen,

(b) C _1-3 alkyl, (c) Ci _-3 alkyl which is optionally partially or fully fluorinated;

R ⁵ up to three substituents which are independently selected from

(a) C _1-3 alkyl,

(b) -OH

means as well as their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts with organic or inorganic acids or bases.

2. Compounds of formula I according to claim 1, in which R ¹ , R ^2a , R ^2b , R ³ , R ⁴ and R ^{5 are} as defined in claim 1 and

A is a direct bond, namely compounds of formula Ia:

as well as their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts with organic or inorganic acids or bases.

3. Compounds of formulas I or Ia according to claim 1 or 2, in which A, R, R

R> 3, n R4 and R are as defined in claim 1 or 2, and

R ^{1 is} a group selected from

means

their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts with organic or inorganic acids or bases.

4. Compounds according to any one of the preceding claims, wherein

A, R, R, R, R and R are as defined in the preceding claims and

R ^{4 is} a group selected from

means

their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts with organic or inorganic acids or bases.

5. Compounds according to one of the preceding claims, wherein A, R ¹ , R ^2b , R ³ , R ⁴ and R ^{5 are} as defined in the preceding claims and

, 2a is hydrogen,

their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts with organic or inorganic acids or bases.

6. Compounds according to one of the preceding claims, wherein A, R ¹ , R ^2a , R ³ , R ⁴ and R ^{5 are defined} as mentioned above under the first embodiment, and

Hydrogen means

their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts with organic or inorganic acids or bases.

7. Compounds according to any one of the preceding claims, wherein

10

15 16

19 20

21 22

23 24

25 26

29 30

31 32

35 36

37 38

39 40

41 42

43 44

45 46

47 48

49 50

51 52

53 54

55 56

57 58

59 60

61 62

63 64

65 66

67 68

71 72

73 74

75 76

81 82

83 84

85 86

87 88

89

their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts with organic or inorganic acids or bases.

8. Physiologically acceptable salts of the compounds according to any one of claims 1 to 7 with inorganic or organic acids or bases.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a physiologically acceptable salt according to claim 8 in addition to optionally one or more inert carriers and / or diluents.

10. Use of a compound according to any one of claims 1 to 8 for the manufacture of a medicament for the acute and prophylactic treatment of acute pain, intestinal pain, neuropathic pain, inflammatory / pain receptor-mediated pain, cancer pain and headache disorders.

1 1. A process for the preparation of a medicament according to claim 9, characterized in that a compound according to at least one of claims 1 to 8 is incorporated into one or more inert carriers and / or diluents by non-chemical means.